MX2007014730A

MX2007014730A - Combinations of a squalene synthase inhibitor and a hmg-coa reductase inhibitor for treating hyperlipidemia.

Info

Publication number: MX2007014730A
Application number: MX2007014730A
Authority: MX
Inventors: Tomoyuki Nishimoto; Ryuichi Tozawa; Takeo Wada; Eiichiro Ishikawa; Toshiya Nishi; Hiroko Yamakawa
Original assignee: Takeda Pharmaceutical
Priority date: 2005-06-01
Filing date: 2006-05-31
Publication date: 2008-02-15
Also published as: WO2006129859A3; EP1962832A2; CR9521A; JP2008542191A; US20090209510A1; MA29531B1; AR054368A1; AU2006253255A1; BRPI0610484A2; RU2007149337A; KR20080012916A; WO2006129859A2; CA2609784A1; NO20076566L; IL187207A0; TW200714280A; PE20070603A1

Abstract

A pharmaceutical composition useful for the prevention and/or treatment of hyperlipidemia, which comprises combining an effective amount of a squalene synthase inhibitor and a HMG-CoA reductase inhibitor is provided. Furthermore, a method for preventing and / or treating hepatic toxicity caused by the administration of a HM6-C0A veductase inhibitor, which comprisis adminisvering an effective amount of a sgualence synthase inhibitor, is provided .

Description

COMBINATIONS OF AN INHIBITOR OF ESCINOEN SYNTHASE AND AN INHIBITOR HMG-COA REDUCTASE FOR THE TREATMENT OF HYPERLIPIDEMIA FIELD OF THE INVENTION The present invention is based on the finding that N- [[(3R, 5S) -1- (3- acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidin -4-acetic (hereinafter, abbreviated as Compound X), which is an inhibitor of squalene synthase (hereinafter referred to as "SSI") and is useful as a preventive and / or therapeutic agent of hyperlipidemia, can potentiate the action of HMG-CoA reductase inhibitor, mainly, "statin" (eg, atorvastatin, lovastatin, simvastatin, pravastatin, etc.) which is widely used clinically at present as a preventive and / or therapeutic agent of hyperlipidemia . The invention further relates to a method for treating hyperlipidemia or the like in mammals including animals or humans by the use of a combination of squalene synthase inhibitor and the HMG-CoA reductase inhibitor. BACKGROUND OF THE INVENTION Hyperlipidemia refers to a state in which the concentration of serum lipid is abnormally high. The serum lipid includes cholesterol, phospholipid, Ref.187595 triglyceride (neutral fat) and the like. Specifically, a clinical problem occurs when cholesterol and triglyceride are elevated. Many epidemiological investigations have clearly shown that hypercholesterolemia is one of the three risk factors for atherosclerotic diseases such as myocardial infarction, angina pectoris, cerebral infarction and the like accompanied by hypertension and smoking. Therefore, proper control of blood cholesterol level is very important in the prevention or treatment of atherosclerotic diseases such as ischemic heart diseases. The abovementioned HMG-CoA reductase inhibitor has been the most widely used clinically so far as a medicament for reducing the level of cholesterol in the blood for the prevention and / or treatment of hyperlipidemia. The current treatment regimen with respect to blood lipid control (NCEP-ATP III, USA, The Japanese Atherosclerosis Society guideline, etc.) suggests that the target therapeutic level for low density lipoprotein cholesterol (LDL) -C, for its acronym in English) of patients who are at high risk for development of ischemic heart disease is less than 100 mg / dl. Even more, the normal level for the triglyceride is less than 150 mg / dl, thus strict control of the lipid However, from recent large-scale test results regarding active LDL-C reducing therapy, it has been shown that reducing the level of LDL-C is effective in decreasing the risk of developing ischemic heart disease even when the level of LDL-C is less than 100 mg / dL (PROVE-IT test, TNT test, etc.). On the other hand, the HMG-CoA reductase inhibitor has clinical risk of side effects based on the fact that it is a drug that inhibits the synthesis of cholesterol in the living being by inhibiting the activity of HMGCoA reductase in the path of cholesterol biosynthesis and reduces the concentration in the blood. Specifically, when H MG-CoA reductase is inhibited, not only the biosynthesis of cholesterol but also the biosynthesis of some other components such as ubiquinone, dolichol and heme A, which are necessary for the living body, are also inhibited, so there is concern about the resulting undesirable side effects (eg, rhabdomyolysis, muscle pain, etc.). Furthermore, collateral effects such as gastrointestinal disturbance and decreased liver function have also been reported. Accordingly, the maximum dosage of HMG-CoA reductase inhibitor to be administered (eg, atorvastatin and simvastatin: up to 80 mg per day, pravastatin: up to 40 mg per day; pitavastatin: up to 2 mg per day) has been decided based on the dosage that manifests liver toxicity or toxicity in the muscle and the safety zone in animals and humans. However, because the administration of the HMG-CoA reductase inhibitor at maximum dose has been accepted for administration in humans, it may have a high frequency of such toxicity, treatment by high dose of HMG-inhibitor. CoA reductase can not be performed. Therefore, in the case of administering it for treatment of hyperlipidemia in the practical medication, it is usual that it is initially administered at a low dosage to a patient and then afterwards a higher dosage is administered only when sufficient results are not obtained with a dosage lower. It is common, in general, to avoid administering a high dose of HMG-CoA reductase inhibitor as much as possible. It is expected that the administration of the highest dose of HMG-CoA reductase inhibitor will possess a potent LDL-C reducing action in order to meet the requirements for blood lipid control under the current treatment regimen. On the other hand, it is a concern that high dose therapy of HMG-CoA reductase inhibitor will increase the risk of manifesting toxicity such as liver toxicity, etc. Additionally, regarding the combination of the HMG-CoA reductase inhibitor and the fibrate drug aimed at reducing triglycerides, has been reported to increase the risk of muscle toxicity such as rhabdomyolysis or the like. Under this circumstance, it is considered that the combination therapy of HMG-CoA reductase inhibitor with a new drug that makes possible the treatment of patients who can not reach the therapeutic target level of LDL cholesterol with a therapy that uses only HMG inhibitor -CoA reductase, which reduces the risk of toxicity of HMG-CoA reductase inhibitor therapy in a high dose and also improves the level of total lipids including triglycerides, can be an important option for prevention and / or treatment of hyperlipidemia. BRIEF DESCRIPTION OF THE INVENTION The present inventors have unexpectedly found in the course of investigation of the various actions of Compound X that this compound, when combined with the HMG-CoA reductase inhibitor, potentiates the action of cholesterol and triglyceride reduction in comparison with the individual administration of the HMG-CoA reductase inhibitor, and reduces the liver toxicity by the HMG-CoA reductase inhibitor, and completed the present invention.

That is, the invention relates to: (1) A method for preventing and / or treating hyperlipidemia comprising administering to a mammal affected with hyperlipidemia a combination of an effective amount of squalene synthase inhibitor and a HMG-CoA inhibitor. reductase; (2) The method according to (1) indicated above, wherein the HMG-CoA reductase inhibitor is administered at a high dose in an accepted dosage; I (3) The method according to (2) above, wherein the HMG-CoA reductase inhibitor is administered at a maximum dose in the accepted dosage; (4) A method for preventing and / or treating liver toxicity caused by the administration of an HMG-CoA reductase inhibitor comprising administering an effective amount of squalene synthase inhibitor to inhibit the toxicity caused by the administration of an inhibitor of HMG-CoA reductase. HMG-CoA reductase to a mammal to which the inhibitor of HMG-CoA I reductase had been administered; , I (5) The method according to the (4) indicated above, wherein the mammal is affected with hyperlipidemia; (6) The method according to (1) or (2) above, wherein the squalene synthase inhibitor i > , I is a compound represented by the formula: wherein, Ri is a hydrogen atom or an optionally substituted hydrocarbon group, R 2 and R 3 are the same or different and are a hydrogen atom, optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X 'is a group comprising optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxy group, an optionally substituted amino group or an optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated, ring A is an optionally substituted benzene ring or an optionally substituted heterocyclic ring, the ring J 'is a 7 or 8 membered heterocyclic ring containing 3 heteroatoms or less as the constituent atoms of the ring, and the ring J' may additionally have a substituent in addition to Ri, R2, R3 and X '; (7) The method according to (1) or (2) above, wherein the squalene synthase inhibitor is N- [[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl)] ) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidin-4-acetic; (8) The method according to (1) or (2) above, wherein the HMG-CoA reductase inhibitor is one or more drugs selected from the group consisting of atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin , cerivastatin and pitavastatin; (9) The method according to (1) or (2) indicated above, wherein the mammal affected with hyperlipidemia is a patient without tolerance to the HMG-CoA reductase inhibitor; (10) The method according to (1) or (2) above, wherein the mammal affected with hyperlipidemia is a patient at high risk of ischemic heart disease; (11) The method according to (1) or (2) indicated above, wherein the mammal affected with hyperlipidemia is a patient affected with familial hypercholesterolemia; (12) A pharmaceutical composition for prevention and / or treatment of hyperlipidemia comprising combining an effective amount of squalene synthase inhibitor and a HMG-CoA reductase inhibitor; (13) A pharmaceutical composition for prevention and / or treatment of hyperlipidemia comprising an effective amount of squalene synthase inhibitor and HMG-CoA reductase inhibitor, which is composed or packaged to be administered in divided doses, sequentially or simultaneously to a mammal affected with hyperlipidemia; (14) The pharmaceutical composition according to the above (12) or (13), which comprises combining it with a high dose in an accepted dosage of HMG-CoA reductase inhibitor; (15) The pharmaceutical composition according to the above (12) or (13), which comprises the combination with a maximum dose in an accepted dosage of the HMG-CoA reductase inhibitor; (16) A method for improving an effect of preventing and / or treating hyperlipidemia by an HMG-CoA reductase inhibitor comprising administering an effective I 'II quantity of squalene synthase inhibitor to a mammal affected with hyperlipidemia where it is administered an effective amount of HMG-CoA reductase inhibitor; (17) The use of the squalene synthase inhibitor for the manufacture of a pharmaceutical composition for preventing and / or treating hyperlipidemia comprising combining an effective amount of squalene inhibitor I synthase and HMG-CoA reductase inhibitor; (18) The use of the squalene synthase inhibitor for the manufacture of a pharmaceutical composition for preventing and / or treating hyperlipidemia comprising an effective amount of squalene synthase inhibitor and HMG-CoA reductase inhibitor which are compounds or packaged to be administered in doses divided, sequentially or simultaneously to a mammal affected with hyperlipidemia; (19) The method according to (1) or (2) above, wherein in addition an effective amount of ezetimibe is administered in combination as a third medication; (20) The pharmaceutical composition according to (12) or (13) indicated above, further comprising the combination of an effective amount of ezetimibe as a third drug; (21) The use of a squalene synthase inhibitor for the manufacture of a pharmaceutical composition for preventing and / or treating hyperlipidemia according to (17) or (18) above, which further comprises the combination with an effective amount of ezetimibe as a third medication; and the similar. Compound X is a known compound described, for example, in JP-A No. 9-136880 (Example 36). It is known that this compound has an action that inhibits squalene synthase, and inhibits a step of the same biosynthesis path of i 'i cholesterol as does the HMG-CoA reductase inhibitor (but located after its action point) to suppress cholesterol biosynthesis, which decreases the concentration of cholesterol in the blood and thus is useful for prevention and / or treatment of hyperlipidemia . JP-A No. 9-136880 discloses that the SSI compounds of the application which include Compound X can be used in combination with various other lipid reducing drugs or cholesterol lowering drugs in the prevention and / or treatment of hyperlipidemia wherein the Use in a combination with the HMG-CoA reductase inhibitor is also mentioned. However, no mention has been made of the active effects of the potentiation of the actions and effects by use in a combination of both in comparison with the individual administration (pharmacological data of any kind are not described). Additionally, it is known that the SSI that includes Compound X has an action of reducing muscle toxicity caused by the HMG-CoA reductase inhibitor such as rhabdomyolysis and the like (WO04 / 064865). In addition, it is known that the SSI that includes Compound X has an action of increasing ubiquinone, so it is effective for the prevention and / or treatment of the disr of organ function and organ failure due to atherosclerosis disease and diseases. cerebrovascular and what similar (WO03 / 002147). However, SSI including Compound X has not been reported to possess an organ protective action for drug-induced organ toxicity, particularly hepatic disr manifested as a side effect of the HMG-CoA reductase inhibitor. For the purposes of the use in combination of Compound X and the HMG-CoA reductase inhibitor, the inventors have found that the actions and effects are significantly enhanced in the animal model by the combination of both as compared to the individual administration as illustrated in the results of pharmacological test series below. The effects of the use in combination of Compound X, SSI and the HMG-CoA reductase inhibitor are indicated to be unexpected and not presumed by conventional recognition. Furthermore, the inventors have also found for the first time that by use in combination of Compound X, SSI, and the HMG-CoA reductase inhibitor, the hepatic toxicity manifested by the HMG-CoA reductase inhibitor can be suppressed as illustrated in pharmacological test results later. From the findings in the animal model described above, the inventors have made an invention that can achieve medical effects such as the following in a human being using SSI and the HMG-CoA inhibitor reductase in combination for prevention and / or treatment of hyperlipidemia. 1) the improvement of serum lipid can be achieved more strongly which can not be achieved by the individual administration of the HMG-CoA reductase inhibitor or SSI respectively. 2) the side effect of the HMG-CoA reductase inhibitor such as muscle toxicity, liver toxicity, or the like can be suppressed. For this reason, the HMG-CoA reductase inhibitor can be administered in a dosage higher than the conventional dosage in a safe manner for patients. For such excellent synergistic effects, treatment with a combination of SSI and the HMG-CoA reductase inhibitor can more effectively control hyperlipidemia compared to treatment exclusively with the HMG-CoA reductase inhibitor. That is, by administering the HMG-CoA reductase inhibitor in combination with SSI, including its maximum dosage, its lipid-reducing action can be enhanced without showing liver toxicity and muscle toxicity which are the drawbacks of the HMG-inhibitor. CoA reductase, while also providing a new method of treating hyperlipidemia in practical medication. In addition, it can be expected that the use in combination with SSI can add a way to administer the i 'inhibitor of HMG-CoA reductase in an amount in addition to the maximum dosage currently approved. It has not been reported so far that the combined use of the HMG-CoA reductase inhibitor with SSI can achieve the merits indicated above in a human or animal test. Accordingly, the invention provides a new use of a squalene synthase inhibitor. DETAILED DESCRIPTION OF THE INVENTION Preferred examples of each definition in the present invention are the following. "Hyperlipidemia" refers to a state in which the concentration of serum lipid rises abnormally. The serum lipid includes cholesterol, phospholipids, triglyceride (neutral fat) and the like. Specifically, there is a clinical problem when cholesterol and triglyceride is elevated. "Hyperlipidemia" includes hypercholesterolemia, hypertriglyceridemia, and the like. As stated above, a superior prophylactic and / or therapeutic effect of hyperlipidemia can be obtained in the present invention, therefore it is suitable for application, inter alia, to severe diseases in hyperlipidemia. For example, it can be applied advantageously to cases where the patient (a mammal) i affected with hyperlipidemia is a patient who has a history of ischemic heart disease, a high-risk patient who has plural risk factors of 'ischemic heart disease such as hypertension,' diabetes, obesity and smoking, or a patient afflicted with familial hypercholesterolemia. i i The "HMG-CoA reductase inhibitor" in the present invention means, what is termed, "statin" such as atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, pitavastatin, cerivastatin, or the like. In the present invention, the term "high dose in an accepted dosage" for the inhibitor of | I I HMG-CoA reductase refers to a dose of the highest dosage type that includes the maximum dose, and when there are several accepted dosages, the term sometimes means plural doses. Generally, the dose is classified under a dose exceeding that normally administered by the HMG-CoA reductase inhibitor to each mammal I having a prevention and / or treatment of hyperlipidemia I by a single administration of HMG-CoA reductase inhibitor. (that is, usual dose), and it varies from one mammal to the other. 'I I The accepted doses of each HMG-CoA reductase inhibitor commercially available at present are the next. Atorvastatin: 10, 20, 40, 80 mg / person / day. Simvastatin: 5, 10, 20, 40, 80 mg / person / day, Pravastatin: 10, 20, 40, 80 mg / person / day. Fluvastatin: 20, 40, 80 mg / person / day, Lovastatin: 10, 20, 40 mg / person / day. Rosuvastatin: 5, 10, 20, 40 mg / person / day. Pitavastatin: 1.2 mg / person / day, Examples of the preferable doses of the "high dose in the accepted dosage" include, but are not limited to, 40, 80 mg / person / day in Atorvastatin, 20, 40, 80 mg / person / day (more preferably 40, 80 mg / person / day) in Simvastatma, 40, 80 mg / person / day in Pravastatin, 40, 80 mg / person / day in Fluvastatin, 20, 40 mg / person / day in Lovastatin, 20, 40 mg / person / day in Rosuvastatin, and 2 mg / person / day in Pitavastatin. The "patient without tolerance to the HMG-CoA reductase inhibitor" refers to, between patients including both a "patient of poor reaction to HMG-CoA reductase inhibitor" wherein the administration of HMG-CoA reductase inhibitor does not demonstrate any insufficient action or effect cholesterol reducer and a patient where the administration is restricted due to a high incidence rate of side effects, patients where a prevention and / or sufficient treatment of hyperlipidemia not can be achieved by a usual treatment (for example, patients who can not achieve the desired value in the current treatment regimen with respect to blood lipid control (NCEP-ATP III, E.U.A., Atherosclerosis Society of Japan, etc.). As the "squalene synthase inhibitor" to be used in the present invention, any compound can be used with the condition having an inhibitory activity of squalene synthase, for example, squalene-statins (for example, U.S. Patent Nos. 5506262, 5430055, 5409950 , 5369125, Japanese Patent Nos. 7-173166, 9-124655, 9-227566, "Annual Review of Microbiology", Vol.49, pp. 607-639, 1995, "Journal of Medicinal Chemistry", Vol.38, p. 3502-3513, 1995, "Journal of Medicinal Chemistry", Vol.39, pp. 207-216, 1996., "Journal of Medicinal Chemistry", Vol.39, pp. 1413-1422, 1996, etc.), a phosphate compound and a carboxylic acid compound of an analogous substrate (e.g., U.S. Patent Nos. 5374628, 5441946, 5428028, Japanese Patent No. 7-041554, WO95 / 04025, "Medical Chemistry Journal", Vol.38 , pp. 2596-2605, 1995, "Arzniemittel-Forschung Drug Research", Vol. 46, p., 759-762, 1996, the "Medi Chemistry Newspaper" cinal ", Vol. 31, p., 1869-1871, 1988," Journal of Medicinal Chemistry ", Vol.39, p. 657-660, 1996, "Journal of Medicinal Chemistry", Vol.39, p., 661- 664, 1996), carboxylic acid derivatives (e.g., O97 / 40006, W096 / 33159, 095/21834, O97 / 48701, EP-A Nos. 645377, 645378, 814080, 790235, JP-A Nos., 7- 173120, 10-316634, 10-298134, 10-298177, 10-316617, 9-136880, O2000 / 00458, WO2001 / 98282, WO98 / 29380, "Letters of Bioorganic Medicinal Chemistry", Vol.5, pp. 1989- 1994, 1995, "Letters of Bioorganic Medicinal Chemistry", Vol.6, pp. 463-466, 1996, "Journal of Medicinal Chemistry", Vol.40, pp. 2123-2125, 1997, etc.), a compound based in amine such as quinuclidine derivatives (e.g., U.S. Patent Nos. 5385912, 5494918, 5395846, 5451596, JP-A Nos., 8-134067, 2000-169474, 10-152453, 2000-502716, O94 / 03541 , WO 94/05660, W095 / 35295, W096 / 26938, W095 / 31458, WO95 / 00146, WO97 / 25043, WO98 / 12170, etc.), and Zaragozic acids, particularly, a compound represented by the formula: wherein, Ri is a hydrogen atom or an optionally substituted hydrocarbon group, R2 and R3 are the same or different and a hydrogen atom, optionally substituted hydrocarbon group or a heterocyclic group optionally substituted, X 'is a group comprising an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxy group, an optionally substituted amino group or an optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated, Ring A is an optionally substituted benzene ring or an optionally substituted heterocyclic ring, Ring J 'is a 7- to 8-membered heterocyclic ring containing 3 heteroatoms or less as ring constituents, and Ring J1 may additionally have a substituent in addition to Ri, R2, R3, and X '; or a compound represented by the formula wherein Ri is a hydrogen atom or an optionally substituted hydrocarbon group, R2 and R3 are the same or different and a hydrogen atom, optionally substituted hydrocarbon group or optionally substituted heterocyclic group, Xi is a bivalent atomic bond or chain, and is an optionally esterified carboxyl group, an optionally substituted carbamoyl group, a hydroxy group optionally substituted, an optionally substituted amino group or an optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated, Ring B is an optionally substituted benzene ring; a compound represented by the formula [II]: (II) wherein ring A and ring B each represents an optionally substituted benzene ring, ring C represents an optionally additionally substituted aromatic ring, Ri represents a lower alkyl group optionally substituted with an optionally substituted hydroxy group, Xla represents a bond or an optionally substituted lower alkylene, Xlb represents a bond or optionally substituted lower alkylene, X2 represents a bond, -O- or -S-, X3 represents a bond or an optionally substituted bivalent hydrocarbon group, and Y represents a carboxyl group optionally esterified or amidated; I or the like is preferably used. Examples of other squalene synthase inhibitors include A-104109 (Abbott Laboratories), F-10863-A (Zaragózico acid D3, Sankyo Co., Ltd.), bisphosphonic acid derivatives such as ER-28448, ER-27856 (prodrug ER-28448), and quinuclidine derivatives (Eisai) such as ER- 119884 and ER-132781, RPR-107393 and RPR-101821 (Aventis Pharma S.A ..) the thiadiazole derivatives (NovoNordisk), the isopropylamine derivatives and quinuclidine derivatives (Yamanouchi Pharmaceutical Co., S.A.), the isoquinuclidine derivatives (pharmaceutical company Kotobuki, S.A.). the malonic acid derivatives (Cia. Nippon Kayaku, S.A ..), propionyl derivatives (Daiichi Pharmaceutical Co., S.A.) wherein R is hydrogen atom or methyl group, SQ-34919, SQ-32709, BMS-187745 and BMS-188494 (Bristol-Myers Squibb Company) wherein R is potassium atom or -CH2OCOC (CH3) 3, J-104118 (Merck &Co., Inc.) the quinuclidine derivatives (AstraZeneca) SDZ-266-806 (Novartis Pharma) and such squalene synthase inhibitors can also be used an agent of the present invention. The "compound having squalene synthase inhibitory activity" used in the present invention can be used in a form of a salt or a prodrug. As for a "salt" of the compound having squalene synthase inhibitory activity used in the present invention, a pharmaceutically acceptable salt or a physiologically acceptable acid addition salt is preferable. For such salts, for example, inorganic acids (for example, hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, etc.) or organic acids (for example, acetic acid, formic acid, propionic acid, fumaric acid) are used. , maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, acid benzenesulfonic, etc.) or similar. Still further, in the case that the "compound possessing squalene synthase inhibitory activity" used in the present invention has an acidic group such as carboxylic acid or the like, the "compound possessing squalene synthase inhibitory activity" can form salts with, for example, an inorganic base (for example, an alkali metal or alkaline earth metal such as sodium, potassium, calcium, magnesium, or ammonium, etc.) or an organic base (for example, trialkylamine of C? -3 such as triethylamine, etc.). The "prodrug" of the compound having squalene synthase inhibitory activity [hereinafter, called "SSI Compound"] used in the present invention or a salt thereof refers to a compound that is converted to the SSI Compound by a reaction in the living being under a physiological condition with an enzyme, a gastric acid or the like, that is, a compound that is converted to the SSI Compound by enzymatic oxidation, reduction, hydrolysis, etc .; a compound that is converted to the SSI Compound by hydrolysis or the like with gastric acid, etc .; or the similar. Examples of the drug component of the SSI Compound include a compound wherein an amino group of the SSI Compound is acylated, alkylated or phosphorylated (for example, a compound wherein an amino group of the SSI Compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, etc.); a compound wherein a hydroxy group of Compound SSI is acylated, alkylated, phosphorylated or boroned (for example, a compound wherein a hydroxy group of Compound SSI is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumedylated, alanylated or dimethylaminomethylcarbonylated, etc. .); or a compound wherein a carboxyl group of the SSI Compound is esterified or amidated (for example, a compound wherein a carboxyl group of the SSI Compound is ethyl esterified, phenylsterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl esterified, ftalidyl esterified, (5-methyl-2 -oxo-1, 3-dioxolen-4-yl) methyl ester, cyclohexyloxycarbonylethersterified or methylamido, etc.); and the similar. These compounds can be prepared from the SSI Compound by a method known per se. Additionally, the prodrug of the SSI Compound may be a compound that is reconstructed in the SSI Compound under physiological conditions such as described in "Development and Pharmaceutical Research," Vol.7 (Molecular Design), p. 163-198, published in 1990 by Hiroka to Publishing Co., In addition, the SSI compound can be hydrated. When the optically active form of the SSI Compound is necessary, it can be obtained, for example, by using an optically active starting material, or using a conventional method to optically resolve the racemic form of the SSI Compound. Still further, when the SSI Compound contains an asymmetric carbon atom in its molecule and has two stereoisomers of R configuration and S configuration, any isomer or mixture thereof is included within the scope of the present invention. In formulas (I) and (la), examples of the hydrocarbon group in the "optionally substituted hydrocarbon group" represented by Ri include an aliphatic chain (acyclic) hydrocarbon group, an alicyclic hydrocarbon group and an aryl group, and among these , the aliphatic chain hydrocarbon group is preferred. The aliphatic chain hydrocarbon group of the hydrocarbon group includes a straight or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group. Among these, the branched alkyl group is preferable. Examples of the alkyl group include C__7 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n- hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 3, 3-dimethylpropyl, 2-ethylbutyl, n-heptyl and the like. Among others, C3.5 alkyl such as n-propyl, isopropyl, isobutyl, neopentyl is preferable, and isobutyl, neopentyl and the like are particularly preferred. Examples of the alkenyl group include C 2-6 alkenyl such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 2-ethyl-l-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl- 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. Among others, vinyl, allyl, isopropenyl, 2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl and the like are particularly preferable. Examples of the alkynyl group include C 2-6 alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl , 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like, among others, ethynyl, 1-propynyl, 2-propynyl and the like are particularly preferred. The alicyclic hydrocarbon group of the hydrocarbon group includes a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and the like. As the cycloalkyl group, a group is preferable C3_9 cycloalkyl, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. Among these, a C3_6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is preferable. Examples of the cycloalkenyl group include a C5-6 cycloalkenyl group such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexene-1-yl, I 1- cyclobuten-1-yl and 1-cyclopenten-1-yl. The group examples! Cycloalkadienyl include a C5-6 cycloalkadienyl group such as 2, -cyclopentadien-1-yl, 2, -cyclohexadien-1-yl and 2, 5-cyclohexadien-1-yl. The aryl group of the hydrocarbon group includes a C6-16 fused polycyclic or monocyclic aromatic hydrocarbon group such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, among others, an aryl group of C 1 -io such as phenyl, 1-naphthyl and -naphthyl are particularly preferred. The substituent of the "optionally substituted hydrocarbon group" represented by Ri includes an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heterocyclic group, an optionally substituted amino group, an optionally substituted hydroxy group, an 1 ! eleven optionally substituted thiol group, a halogen atom (eg, fluorine, chlorine, bromine, iodine) and oxo etc., and the hydrocarbon group is optionally arbitrarily substituted with 1 to 5 (preferably 1 to 3) of these substituents in a substitutable position . Examples of the aryl group of the optionally substituted aryl group include an aryl group of Cs-16 such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, inter alia, a C6-? Aryl group or such as phenyl, with 1-naphthyl being preferable and 2-naphthyl. The substituent of the optionally substituted aryl group includes a C3_3 alkoxy group (e.g., methoxy, ethoxy, ethoxy, etc.), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), an alkyl group of C ? -3 (for example, methyl, ethyl, propyl, etc.) and the like, and the aryl group is optionally substituted arbitrarily with 1 to 2 of these substituents. Examples of the cycloalkyl group of the optionally substituted cycloalkyl group include a C3_7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. As for the substituent of the optionally substituted cycloalkyl group and the number of substituents, the same type and number as the substituent for the above-mentioned optionally substituted aryl group can be exemplified. Examples of the cycloalkenyl group of the optionally substituted cycloalkenyl group include a C3_6 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. As for the substituent of the optionally substituted cycloalkenyl group and the number of substituents, the same type and number as the substituents for the above-mentioned optionally substituted aryl group can be exemplified. A heterocyclic group of the optionally substituted heterocyclic group includes an aromatic heterocyclic group and a saturated or unsaturated non-aromatic heterocyclic group (heterocyclic aliphatic group) containing at least one and preferably 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as a constituent atom of the ring system (ring atom), and an aromatic heterocyclic group is preferred. The ? examples of the aromatic heterocyclic group include a 5- to 6-membered aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2, 4-Oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazole, 1,2-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2 , 4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) and a fused aromatic heterocyclic group I in which 2 to 3 of the 5 to 6 membered rings are fused (for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H- 1 indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthizinyl, purinyl, pteridinyl, carbazolyl, a-carbolinyl, β-carbolinyl, ? -carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thiantrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2- b] pyridazinyl, imidazo [1,2- a] pyrimidinyl, 1,2,4-triazolo [4, 3-a] pyridyl, 1 2,4-triazolo [4, 3-b] pyridazinyl, etc.), among others, a 5- to 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl and pyrimidinyl is preferred. . Examples of the non-aromatic heterocyclic group include a 4- to 8-membered non-aromatic heterocyclic group such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl. The optionally substituted heterocyclic group may have 1 to 4, preferably 1 to 2 substituents, and such substituents include the C? _3 alkyl group (for example, methyl, ethyl, propyl, etc.) and the like. As the 1 I substituent on the optionally substituted amino group (including amino group, mono- or disubstituted amino group), optionally substituted hydroxy group and optionally substituted thiol group, a lower alkyl (Cl-3) (eg, methyl, ethyl, propyl, etc.) and the like are exemplified. Still further, when the hydrocarbon group in the optionally substituted hydrocarbon group represented by Ri is an alicyclic hydrocarbon group or an aryl group, the substituent may also be an alkyl group of C? _ (For example, methyl, ethyl, propyl, etc. .). Additionally, as described above, Ri may have an oxo group as a substituent, and an acyl group of carboxylic acid which is such as a hydrocarbon group substituted with oxo included in R1 # Examples thereof include an acyl group of C? -6 optionally substituted (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, dimethylacetyl, trimethylacetyl, etc.) and the like. Still further, the acyl group may have 1 to 5 substituents in a substitutable position, and the substituent includes a halogen atom (e.g., fluorine, chlorine, bromine). In formulas (I) and (la), the "optionally substituted hydrocarbon group" represented by R2 and R3 may include the group described as "optionally substituted hydrocarbon group" represented by Ri. However, an alkyl group, an aryl group and the substituents of the They can be the group as the following. That is, as to the alkyl group of the "optionally substituted alkyl group", a lower C C_6 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) is exemplified. , pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), and preferably an C? -4 alquilo alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl is exemplified. For example, this optionally substituted alkyl group may have 1 to 4 substituents, and such substituents include a halogen atom (e.g., fluorine, chlorine, bromine, iodine), lower alkoxy group C? _ (E.g., methoxy, ethoxy, propoxy) , isopropoxy, butoxy, tert-butoxy, etc.) and the like. The "optionally substituted aryl group" includes the fused polycyclic or fused monocyclic aromatic hydrocarbon group such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, and among them, phenyl is particularly preferred. The substituent of the "optionally substituted aryl group" includes a halogen atom (eg, fluorine, chlorine, bromine, iodine etc.), optionally substituted lower alkyl group, optionally substituted lower alkoxy group, an optionally substituted hydroxy group, nitro and cyano, and can be substituted with 1 to 3 (preferably 1 to 2) of these same or different substituents. Examples of the lower alkyl include an alkyl group of C? 4 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, among others, methyl and ethyl are particularly preferred. Examples of the lower alkoxy include a C ?4 alkoxy group such as methoxy, ethoxy, n-ethoxy, isoethoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, among others, methoxy and ethoxy are particularly preferred. The substituent of the optionally substituted lower alkyl and the optionally substituted lower alkoxy includes a halogen atom (eg, fluorine, chlorine, bromine, iodine etc.), and can be substituted with 1 to 5 in an arbitrary substitutable position. Examples of the substituent on the optionally substituted hydroxy group include a lower (C? -4) alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl etc.), a cycloalkyl group of C3-β ( for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an aryl group of Ce-io (for example, phenyl, 1-naphthyl, 2-naphthyl, etc.) and an aralkyl group of C7 ~ 2 (by example, benzyl, phenethyl, etc.). Still further, these substituents can be combined together with the adjacent substituent to form a ring, and when the aryl group of the "optionally substituted aryl group" represented by R2 and R3 is a phenyl group, a group represented by it can be used, and in addition, such groups can be substituted with 1 to 4 lower (C? _3) alkyl groups (for example, methyl, ethyl, propyl, isopropyl, etc.) and the like. The heterocyclic group of the "optionally substituted heterocyclic group" represented by R2 and R3 includes the heterocyclic group described in detail for the "optionally substituted heterocyclic group" given as a substituent for the "optionally substituted hydrocarbon group" represented by Rx. Among these, a 5- to 6-membered aromatic monocyclic heterocyclic ring such as furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl and imidazolyl are particularly preferred. The substituent for the heterocyclic group includes C? _3 alkyl (e.g., methyl, ethyl, propyl, etc.), and said heterocyclic ring may have 1 to 4 such substituents. Among the above, for R2 and R3, an optionally substituted phenyl group is preferable, a substituted phenyl group is more preferable, and particularly, a 'phenyl group substituted with 1 to 3, preferably 1 to 2, of a halogen atom is preferred. such as chlorine and bromine, lower alkoxy (C? -3) or the like. Still further, any of R2 and R3 is preferably a hydrogen atom.

In the formula (I), the "group comprising an optionally esterified carboxyl group" represented by X 'includes an optionally esterified carboxyl group and a group possessing an optionally esterified carboxyl group. The optionally esterified carboxyl group includes the same group as defined with respect to Y i above. i The "group comprising an optionally substituted carbamoyl group i" represented by X 'includes an optionally substituted I carbamoyl group and a group having an optionally substituted carbamoyl group. The optionally substituted carbamoyl group includes the same group as defined with respect to Y above. The group comprising an "optionally substituted hydroxy group" represented by X 'includes an optionally substituted hydroxy group and a group possessing an optionally substituted hydroxy group. The hydroxy group, optionally substituted, includes the same group as defined with respect to Y above. The "group comprising an optionally substituted amino group" represented by X 'includes an optionally substituted amino group and a group possessing an optionally substituted amino group. The optionally substituted amino group includes the same group as defined with respect to Y above.

The "group comprising an optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated" represented by X 'includes an optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated (i.e., having an active proton) ) and a group having an optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated. The optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated includes the same group as defined with respect to Y above. X 'includes a group represented by formula (a): wherein, X is a bond, or bivalent or trivalent atomic chain, Y is an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxy group, an optionally substituted amino group, or an optionally substituted heterocyclic residue having an hydrogen atom that can be deprotonated, and the dotted line is a single or double bond. In formula (a), the "bivalent atomic chain" represented by X can be any bivalent chain having 1 to 7 preferably, and more preferably 1 to 4. atoms that make up the linear portion, and can have a side chain. An example thereof includes a group represented by where, m and n represent an integer of value 0,, 1, 2 or 3, independently, E represents a bond or atom of an oxygen, a sulfur atom, sulfoxide, sulfone, IN (R5) -, -NHCO-, - CON (R6) - or -NHCONH-. In the present, R 4 and R 6 represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group. 'Additionally, R5 represents a hydrogen atom, a group | lower alkyl, an aralkyl group or an acyl group. , The alkyl group of the "optionally substituted lower alkyl group" represented by R4 and R6 includes a linear or branched lower alkyl group Cl-6 (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ter) -butyl, n-pentyl, isopentyl, neopentyl, etc.). The optionally substituted lower alkyl group may have 1 to 4, preferably 1 to 2 substituents, and examples of such substituents include an aromatic heterocyclic group, (e.g., aromatic heterocyclic ring of 5 to 6 I members containing 1 to 4 heteroatoms of N, O and S as furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl and imidazolyl), an optionally substituted amino group, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally esterified carboxyl group and a halogen atom (e.g., fluorine, chlorine, bromine, iodine). The substituent on the optionally substituted amino group (including an amino group, mono- or di-substituted amino group), an optionally substituted hydroxy group and an optionally substituted thiol group includes lower (Cl-3) alkyl (e.g., methyl, ethyl, propyl) , etc.). Examples of the optionally esterified carboxyl group include C2-5 alkoxycarbonyl such as ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, phenoxycarbonyl and 1-naphthoxycarbonyl, and C7-11 aryloxycarbonyl, and preferably, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl are exemplified. The aralkyl group of the "optionally substituted aralkyl group" represented by R 4 and R 6 includes a C 7 -C 15 aralkyl group such as benzyl, naphthylmethyl, phenylpropyl and phenylbutyl. The optionally substituted aralkyl group may have 1 to 4, preferably 1 to 2 substituents, and such substituents include a halogen atom (e.g., fluorine, chlorine, bromine, iodine), an alkoxy group of Cl-3 (e.g., methoxy group) , ethoxy, ethoxy), a hydroxy group, an amino group, a carboxyl group, a group sulfhydryl, etc. The substituent of the "optionally substituted phenyl group" represented by R4 and R? includes a halogen atom (eg, fluorine, chlorine, bromine, iodine), a C3_3 alkoxy (eg, methoxy, ethoxy, ethoxy, etc.), C3_3 alkyl (eg, methyl, ethyl, propyl). With the proviso that, R4 can be different in each methylene chain. Additionally, the examples of the "lower alkyl group" and the "aralkyl group" represented by R5 include a C 1 - lower alkyl group (e.g., methyl, ethyl, propyl, butyl, tert-butyl, etc.), an aralkyl group of C7-15 (for example, benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, etc.), respectively. Examples of the "acyl group" represented by R5 include a lower (C6-6) alkanoyl group (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), an alkanoyl group ( C3_) lower (eg, acryloyl, methacryloyl, crotonoyl, isocrotonoyl, etc.), a cycloalkancarbonyl group of C4_ (eg, a cyclopropanecarbonyl group, a cyclobutanecarbonyl group, a cyclopentanecarbonyl group, a cyclohexanecarbonyl group, etc.), a group lower alkanesulfonyl (Cl-4) (eg, mesyl, ethanesulfonyl, propansulfonyl, etc.), an aroyl group of C7_ 1 (for example, benzoyl, p-toluoyl, 1-naphthoyl, 2-naphthoyl, etc.), an aryl group of C6-β or lower C2_4 alkanoyl (for example, phenylacetyl, phenylpropionyl, hydroatropoyl, phenylbutyryl, etc.) , an alkenoyl (C3-5) C C-xo lower aryl group (e.g., cinnamoyl, atropoyl, etc.), a C 6 -α-arenesulfonyl group (e.g., a benzenesulfonyl, p-toluenesulfonyl group, etc.) . In addition, X can be a hydrocarbon chain having a double bond or -L-CH (OH) - (L represents a bond or a straight or branched alkylene chain). Examples of the "hydrocarbon chain having a double bond" include a hydrocarbon chain having, preferably 1 to 7, more preferably 1 to 4 carbon atoms that make up the linear portion, and may also have a side chain. The double bond in the hydrocarbon chain is contained in either one or both of a linear portion and a branched portion, and preferably contained in the linear portion. Furthermore, the number of double bonds contained in the hydrocarbon chain is not particularly limited, if possible, but 1 to 2 is preferable. Examples of the hydrocarbon chain having double bond include methine, vinylene, propenylene, butenylene, butadienylene, methylpropenylene, ethylpropenylene, propylpropenylene, methylbutenylene, ethylbutenylene, i I propylbutenylene, methylbutadienylene, ethylbutadienylene, propylbutadienylene, pentenylene, hexenylene, heptenylene, pentadienylene, hexadienylene, heptadienylene and the like, and preferably, methine, vinylene, propenylene, butenylene and butadienylene are exemplified. At present, when the hydrocarbon chain is trivalent, the hydrocarbon chain forms a double bond with a substitutable carbon atom in the ring of ring J '. Examples of the "linear or branched alkylene chain" represented by L include a linear or branched C ?_6 alkylene chain, for example, a bivalent group such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, propylene , ethylmethylene, ethylethylene, propylethylene, butylethylene, methyltetramethylene and methyltrimethylene, and preferably, a C? _3 chain such as methylene, ethylene, trimethylene and propylene is exemplified. Among these, X 'is preferably a group represented by formula (b): - x-Y wherein Xi represents a bond or a bivalent atomic chain, Y represents an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxy group, an optionally substituted amino group or an optionally substituted heterocyclic group which has a hydrogen atom which can be deprotonated. In the formula (b), as for the bivalent atomic chain represented by Xx, the same can be exemplified as in the bivalent atomic chain defined with respect to the aforementioned X. In formulas (a) and (b), the "bivalent atomic chain" represented by X or Xx includes a linear or branched alkylene chain preferably having 1 to 7 (more preferably 1 to 4) carbon atoms constituting the portion linear. Examples of the alkylene chain include a bivalent group such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, propylene, ethylmethylene, ethylethylene, propylethylene, butylethylene, methyltetramethylene and methyltrimethylene, and preferably, a C chain is exemplified. 4 such as methylene, ethylene, trimethylene and propylene. In formulas (a) and (b), the "optionally esterified carboxyl group" represented by Y includes a lower C 2-7 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, sec. butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, etc.), C 1-14 aryloxycarbonyl (for example, phenoxycarbonyl, 1-naphtoxycarbonyl) and Cs-α 2 aralkyloxycarbonyl (for example, benzyloxycarbonyl, etc.). Among these, a carboxyl, methoxycarbonyl, and ethoxycarbonyl group are preferred. The substituent of the "optionally substituted carbamoyl group" represented by Y includes an optionally substituted lower alkyl (C? -e) (for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), an optionally substituted C3_6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an optionally substituted C6_? 4 aryl group (eg, phenyl, -naphthyl, 2-naphthyl, etc.) and an aralkyl group of C7_ ?? optionally substituted (eg, benzyl, phenethyl, etc.), and the carbamoyl group can be substituted with 1 to 2 of these same or different substituents. Substituents on optionally substituted lower alkyl (C6-6) and optionally substituted C3_6 cycloalkyl include a carboxyl group optionally esterified with lower (C1-5) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, pentyl, isopentyl, neopentyl), a 5-6 membered aromatic heterocyclic group containing 1 to 4 heteroatoms (eg, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), an amino group, a hydroxy group and a phenyl group, and 1 to 3 of these same or different substituents can be substituted. The optionally substituted aryl substituent group and the optionally substituted aralkyl group include a halogen atom (eg, fluorine, chlorine, bromine, iodine), and the carboxyl group optionally esterified with a lower C? _4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.). Additionally, in the optionally substituted carbamoyl group, the two substituents on the nitrogen atoms together with the nitrogen atoms can be combined to form a cyclic amino group, and examples of such a cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl , piperidino, morpholino, 1-piperazinyl and the like. Still further, the cyclic amino group may also have a substituent. The substituent of the "optionally substituted hydroxy group" represented by Y includes, for example, lower (C? -) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), a C3 cycloalkyl -6 are grouped (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), a C6- or optionally substituted aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.) and an aralkyl of C7- ?? optionally substituted (for example, benzyl, phenethyl, etc.). The substituent of the optionally substituted aryl group and the optionally substituted aralkyl group includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine), carboxyl group optionally esterified with a lower (C? 4) alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), and the like. The "optionally substituted amino group" represented by Y includes a mono-substituted and di-substituted amino group, and examples of such a substituent include lower (C? 4) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), a C3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an optionally substituted C6- [alpha] aryl are grouped (eg, phenyl, 1- naphthyl, 2-naphthyl, etc.), an aralkyl group of C_ ?? optionally substituted (for example, benzyl, phenethyl, etc.) and the like. Substituents of the optionally substituted aryl group and the optionally substituted aralkyl group include a halogen atom 1 (for example, fluorine, chlorine, bromine, iodine), carboxyl group optionally esterified with a lower (C 4) alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) and the like, and 1 to 4, preferably 1 to 2, of these substituents may possess. Additionally, two substituents on the nitrogen atom can be combined together with the nitrogen atom to forming a cyclic amino group, and examples of such a cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl. Additionally, the cyclic amino group may also have an additional substituent. The heterocyclic residue of the "optionally substituted heterocyclic group" possessing a hydrogen atom that can be deprotonated "represented by Y includes a 5- to 7-membered monocyclic heterocyclic residue (preferably 5 members) having at least one selected from N, S and O (preferably a heterocyclic nitrogen-containing residue) having a hydrogen atom that can be removed to form a proton Examples thereof include tetrazol-5-yl or group represented by the formula: where, i represents -O- or -S-, j represents > C = 0, > C = S or > S (0) 2, (among these, 2,5-dihydro-5-oxo-l, 2, -oxadiazol-3-yl, 2,5-dihydro-5-thioxo-l, 2,4-oxadiazole are preferred. 3-yl and 2,5-dihydro-5-oxo-l, 2,4-thiadiazol-3-yl). The above heterocyclic residue can be protected with an optionally substituted lower alkyl group (preferably C? _4 alkyl) or an acyl group.

Examples of the optionally substituted lower alkyl group include C? _4 alkyl optionally substituted with 1) phenyl optionally substituted by C?-3 alkyl, nitro or C? _3 alkoxy or 2) C?-3 alkoxy (e.g., methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.). Examples of the acyl group include lower (C2-5) alkanoyl, benzoyl and the like. Among these, X 'is preferably an alkyl group substituted with an optionally esterified carboxyl group, an alkyl group substituted with an optionally substituted heterocyclic residue having a hydrogen that can be deprotonated or an alkyl group substituted with an optionally substituted carbamoyl group. In the formula (I), the heterocyclic ring represented by ring A includes a heterocyclic group described in detail with respect to the hydrocarbon group substituent represented by Rx. Among them, a group represented below is preferable.

The substituent of the "optionally substituted benzene ring" "optionally substituted heterocyclic ring" represented by Ring A includes a halogen atom (eg, fluorine, chlorine, bromine, iodine), an optionally substituted C? _4 lower alkyl group (eg, methyl, ethyl, propyl, butyl, tertbutyl, etc.), a lower alkoxy group C 4 optionally substituted (for example, methoxy, ethoxy, ethoxy, isoethoxy, butoxy, tert-butoxy, etc.), a hydroxy group, a nitro and cyano group. Ring A can have 1 to 3, preferably 1 to 2, of these substituents. Even more, these substituents can be combined together with the adjacent substituents to form a ring. The substituent of the optionally substituted lower alkyl group and the optionally substituted lower alkoxy group includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and the like, and 1 to 3 of the substituents may be present in an arbitrary position. Ring A is preferably substituted with methoxy or a chlorine atom, and ring A substituted with a chlorine atom is particularly preferred. In the formula (la), the substituent of the "optionally substituted benzene ring" represented by Ring B includes a halogen atom (eg, fluorine, chlorine, bromine, iodine), an optionally substituted C alquilo -4 inferior lower alkyl group (for example, methyl, ethyl, propyl, butyl, tertbutyl, etc.), an optionally substituted C? -4 alco lower alkoxy group (e.g., methoxy, ethoxy, ethoxy, isoethoxy, butoxy, tert-butoxy, etc.) , a hydroxy group, a nitro group and cyano. Ring B can have 1 to 3, preferably 1 to 2, of these substituents. Still further, these substituents can be combined together with the adjacent substituent to form a ring. The substituent of the optionally substituted lower alkyl group and the optionally substituted lower alkoxy group includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and the like, and 1 to 3 of these substituents may be present in an arbitrary position. Ring B is preferably substituted with methoxy or a chlorine atom, and Ring B substituted with a chlorine atom is particularly preferable. In the formula (I), the heterocyclic ring in the "7- to 8-membered heterocyclic ring containing 3 heteroatoms or less as the constituent atoms of the ring" represented by the ring J 'includes, for example, a saturated or unsaturated heterocyclic ring of 7 or 8 members containing at least one selected from O, S (0) q (q represents 0, 1 or 2) and N. However, the heteroatoms in the atoms constituting the ring of said heterocyclic ring (constitutive atom of ring) are three or less. In addition, Ring J 'can have 1 to 2 substituents in a substitutable position in addition to a group represented by Rlf R2, R3 and X'. When the substituent is attached to a nitrogen atom in Ring J ', the examples of the substituent include an alkyl group (eg, C? _6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc.), a acyl group (for example, acyl group of C? _4 such as formyl, acetyl, propionyl, butyroyl, etc.). The alkyl group or acyl group can be further substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine). Still further, when the substituent is attached to a carbon atom in Ring J ', examples of the substituent include oxo, thioxo, an optionally substituted hydroxy group and an optionally substituted amino group. As for the optionally substituted hydroxy group and optionally substituted amino group, the same as the "optionally substituted hydroxy group" and "optionally substituted amino group" defined as Y above can be exemplified. Ring J 'is preferably substituted with oxo or thioxo to a substitutable position in addition to the group represented by Rx, R2, R3 and X1. Examples of a fused ring comprising Ring A and ring J 'include The formula (I) is preferably a group represented by the formula (I ') where Rlf R2, R3, X 'and ring A are the same as defined above, and Ring Jx represents a 7-membered heterocyclic ring, Zx represents -N (R7) - (R7 represents a hydrogen atom, a group alkyl or an acyl group), -S (0) q (q represents 0, 1 or 2), -CH2- or -O-, K represents C or N, and G represents O or S. In the formula (I1) preceding, the alkyl group represented by R7 includes a straight or branched C?-6 lower alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc.) which can be substituted with 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine). Examples of the acyl group represented by R7 include an acyl group of C? -4 (eg, formyl, acetyl, propionyl, butyroyl, etc.) which can be substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine , bromine, iodine). In the formula (I '), Z is preferably S (0) q (q represents 0, 1 or 2) or O. In addition, K is preferably C and G is preferably O. As for the formula (I'). a compound represented by the formula (I ''). wherein, Rx, R2, R3, Xx, Y and ring A are the same as defined above, and Z2 represents S (0) q (q represents 0, 1 or 2) or O, is more preferable. The compound represented by the formula (I) is preferred compound represented by the formula (la1) wherein, R and Ring B are the same as defined above, and Q represents a hydrogen atom or a metal ion, Ring C represents an optionally substituted phenyl group. In the formula, the substituents at positions 3 and 5 represent trans facing the opposite direction relative to the plane of the 7-membered ring, and (R) represents the configuration R. In the formula (la '), the metal ion represented by Q includes a sodium ion, a potassium ion, a calcium ion, an aluminum ion and the like, among others, are i preferable a sodium ion and a potassium ion. The substituent of the "optionally substituted phenyl group" represented by Ring C includes the same group as the substituent of the "optionally substituted aryl group" described as an example of the "optionally substituted hydrocarbon group" defined above with respect to R2 and R3. Examples of the salt of the compound represented by the formula (I) include the pharmacologically acceptable salts such as an inorganic salt such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, an organic acid salt such as acetate, tartrate, citrate, fumarate, maleate , toluenesulfonate and methanesulfonate, a metal salt such as sodium salt, potassium salt, calcium salt and aluminum salt, and a salt with a base such as triethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine and cinchonin salt. Among these, a sodium salt is preferable. Specific examples of the compound represented by the formula (I) are included below: (3R, 5S) -7-cyano-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1,2 acid 3, 5-tetrahydro-4, 1-benzoxazepin-3-acetic, (3R, 5S) -7-cyano-5- (2,4-dimethoxyphenyl) -1-neopenty1-2-oxo-1, 2,3 acid , 5-tetrahydro-4, 1-benzoxazepin-3 acetic acid (3R, 5S) -7-cyano-5- (2,3-methylenedioxyphenyl) -1- ii neopentyl-2-oxo-l, 2,3,5-tetrahydro-4, 1-benzoxazepin-3 acetic, l (3R, 5S) -7-cyano-5- (2, 3-ethylenedioxyphenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-4, 1-benzoxazepin-3 acetic acid (3R, 5S) -7-cyano-5- (2,3-dimethoxyphenyl) -1-? isobutyl-2-oxo-l, 2,3,5-tetrahydro-4, 1-benzoxazepin-3-acetic, (3R, 5S) -7-cyano-5- (2, -dimethoxyphenyl) -1-isobutyl- 2-oxo-l, 2, 3, 5-tetrahydro-4, l-benzoxazepin-3-acetic, • (3R, 5S) -7-cyano-5- (2,3-methylenedioxyphenyl) -1-isobutyl- 2-oxo-l, 2,3,5-tetrahydro-4, 1-benzoxazepin-3-acetic, i '(3R, 5S) -7-cyano-5- (2,3-ethylenedioxyphenyl) -1-isobutyl -2-oxo-l, 2, 3, 5-tetrahydro-4, l-benzoxazepin-3-acetic, (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl- 2-oxo-l, 2,3,5-tetrahydro-4, 1-benzoxazepin-3-acetic acid, (3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1- i neopentyl-2-oxo-l, 2, 3, 5-tetrahydro-4, l-benzoxazepin-3-X1-acetic acid (3R, 5S) -7-chloro-5- (2,3-methylenedioxyphenyl) -1- neopentyl-2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3] acetic, • (3R, 5S) -7-chloro-5- (2,3-ethylenedioxyphenyl) -1 acid - neopenti1-2-oxo-1, 2,3,5-tetrahydro-4, 1-benzoxazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-isobuty1 -2-oxo-1, 2,3,5-tetrahydro-, 1-benzoxazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2,4-dimethoxyphenyl) -1-isobutyl-2 -oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2,3-methylenedioxyphenyl) -1-isobutyl-2- oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2,3-ethylenedioxyphenyl) -1-isobutyl-2-oxo -l, 2,3,5-tetrahydro-, 1-benzoxazepin-3-acetic acid (3R, 5S) -7-cyano-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-l , 2, 3, 5-tetrahydro-4, l-benzothiazepin-3-acetic acid, (3R, 5S) -7-cyano-5- (2, -dimethoxyphenyl) -1-neopenti1-2-oxo-1, 2 , 3, 5-tetrahydro-4, 1-benzothiazepin-3-acetic acid, (3R, 5S) -7-cyano-5- (2,3-methylenedioxyphenyl) -1-neopentyl-2-oxo-l, 2, 3, 5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S) -7-cyano-5- (2,3-ethylenedioxyphenyl) -1-neopentyl-2-oxo-l, 2,3, 5- tetrahydro-4, 1-benzothiazepin-3-acetic acid (3R, 5S) -7-cyano-5- (2,3-dimethoxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro -4, 1-benzothiazepin-3-acetic, (3R, 5S) -7-cyano-5- (2, -dimethoxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzothiazepin-3-acetic acid, acid ( 3R, 5S) -7-cyano-5- (2,3-methylenedioxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzothiazepin-3-acetic acid (3R) , 5S) -7-cyano-5- (2, 3-ethylenedioxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S ) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S) - 7-Chloro-5- (2,4-dimethoxyphenyl) -1-neopentyl-2-oxo-l, 2, 3, 5-tetrahydro-, l-benzothiazepin-3-acetic acid (3R, 5S) -7- chloro-5- (2, 3-methylenedioxyphenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S) -7-chloro- 5- (2, 3-ethylenedioxyphenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- I-isobutyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzothiazepin-3-acetic acid (3R, 5S) - 7-chloro-5- (2, -dimethoxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-4, 1-benzothiazepin-3- acetic acid (3R, 5S) -7-chloro-5- (2,3-methylenedioxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid, (3R, 5S) -7-chloro-5- (2, 3-ethylenedioxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid, acid ( 3R, 5S) -7-cyano-5- (2-chlorophenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzoxaze in-3-acetic, acid (3R, 5S ) -7-cyano-5- (2-chlorophenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (3R, 5S) -7 -chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (3R), 5S) -7-chloro-5- (2-chlorophenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid (3R, 5S) -7-cyano-5- (2-chlorophenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S) -7-cyano -5- (2-chlorophenyl) -1-isobutyl-2-oxo-l, 2, 3, 5-tetrahydro-4, l-benzothiazepin-3-acetic, acid (3R, 5S) -7-chloro-5- (2-chlorophenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2-chlorophenyl) ) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) ) -1-neopenti1-2-oxo-1, 2,3,5-tetrahydro-, 1-benzoxazepin-3- acetic acid (3R) -7-chloro-5- (2-chlorophenyl) -2,3-dihydro-l-isobutyl-2-oxo-lH-l, 4-benzodiazepin-3-acetic acid (3R, 5S) ) -7-chloro-5- (2-chlorophenyl) -2, 3,4,5-tetrahydro-l-isobutyl-2-oxo-lH-l, 4-benzodiazepin-3-acetic, N- [[(3R , 5S) -7-chloro-5- (2-chlorophenyl) -l-neopentyl-2-oxo-1, 2,3,5-tetrahydro-4, l-benzothiazepin-3-yl] -acetyl] glycine, ( 3R, 5S) -7-chloro-5- (2-chlorophenyl) -3-dimethylaminocarbonylmethyl-l-neopentyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzothiazepine, 7-chloro- 5- (2-chlorophenyl) -l-isobutyl-2-oxo-2,3,4,5-tetrahydro-1H- [1] -benzazepin-3-acetic acid (3R, 5S) -7-chloro-5 - (2-chlorophenyl) -1-neopentyl-1,2,3,5-tetrahydro-2-thioxo-4,1-benzoxazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2 -chlorophenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepin-3-acetic acid (3R, 5S) -7-chloro -5- (2-methoxyphenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepin-3-acetic acid (3R, 5S) ) -7-chloro-l-isobutyl-5- (2-meto) xyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-thieno [2,3-e] oxazepin-3-acetic acid (3R, 5S) -7-chloro-5- (3 -hydroxy-2-methoxyphenyl) -1-neopenty1-2-oxo-1, 2,3,5-tetrahydro-4, 1-benzothiazepin-3-acetic, (3R, 5S) -7-chloro-5- (4-hydroxy-2-methoxyphenyl) -l-neopentyl-2-oxo-l, 2,3,5-tetrahydro-4, l-benzothiazepin-3-acetic acid , (3R, 5S) -7-chloro-5- (3-hydroxy-2-methoxyphenyl) -1- isobutyl-2-oxo-1, 2,3,5-tetrahydro-4,1-benzothiazepin-3 acid -acetic acid (3R, 5S) -7-chloro-5- (4-hydroxy-2-methoxyphenyl) -l-? sobutyl-2-oxo-l, 2, 3, 5-tetrahydro-4, 1-benzothia zepin-3-acetic acid (3R, 5S) -7-chloro-5- (3-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-, 1- benzothia zepin-3-acetic acid (3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-neopentyl-2-oxo-l, 2,3,5-tetrahydro-4, 1-benzothiazepin-3-acetic acid, (3R, 5S), -7-chloro-5- (3-ethoxy-2-methoxyphenyl) -1-isobutyl-2-oxo-l, 2, 3, 5-tetrahydro- 4, l-benzothiazepin-3-acetic acid, (3R, 5S) -7-chloro-5- (4-ethoxy-2-methoxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5- tetrahydro-4, 1-benzothia zepin-3-acetic acid (3R, 5S) -7-chloro-5- (2-chloro-3-methoxyphenyl) -1-neopentyl-2-oxo-l, 2,3, 5-tetrahydro-4, 1-benzot ia zepin -3-acetic acid (3R, 5S) -7-chloro-5- (2-chloro-4-methoxyphenyl) -1- III neopenti1-2-oxo-1, 2,3, 5-tetrahydro-, 1-benzothiazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2-chloro-3-methoxyphenyl) -1 -isobutyl-2-oxo-l, 2,3, 5-tetrahydro-, 1-benzothiazepin-3-acetic, (3R, 5S) -7-chloro-5- (2-chloro-4-methoxyphenyl) -1 acid -isobutyl-2-oxo-l, 2,3,5-tetrahydro-, l-benzot? azep? n-3-acetic acid (3R, 5S) -7-chloro-5- (2-chloro-3-) hydroxyphenyl) -1-neopenty1-2-oxo-1, 2,3,5-tetrahydro-4,1-benzothiazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2-chloro-4) -hydroxy-phenyl) -1-neopentyl-2-oxo-1, 2,3,5-tetrahydro-4,1-benzothiazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2-chloro- 3-hydroxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzothiazepin-3-acetic acid (3R, 5S) -7-chloro-5- (2-chloro) -4-hydroxyphenyl) -1-isobutyl-2-oxo-l, 2,3,5-tetrahydro-4,1-benzothiazepin-3-acetic acid; and you come out of them. The compounds represented by the formula (I) and I the salts thereof [hereinafter sometimes abbreviated as Compound (I) including salts] are described in, for example, EP-A-567026, W095 / 21834 (patent request Japanese No. 6-15531), EP-A-645377 (Japanese Patent Application No. 6-229159), EP-A-645378 (Japanese Patent Application No. 6-229160), and can be prepared according to the description of these publications. The compound represented by the formula (I) is preferably the compound represented by the formula (Ib): Preferable examples of the compound represented by the formula (Ib) include: the compound wherein Rb is a C? -6 alkyl group which may have 1 to 3 substituents selected from the group hydroxy, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy; the compound wherein Rb is a branched C3-6 alkyl group which may have 1 to 3 substituents selected from the group hydroxy, acetyloxy, propionyloxy, t-I-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy; the compound wherein Rb is 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl or 3-Acetoxy-2-acetoxymethyl-2-methylpropyl; the compound wherein Rib is methyl; the compound wherein W is a chlorine atom; the compound wherein Xb is a group represented by the formula: wherein, R 2b and R 3b are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group, or R 2b and R 3b can be combined together with the adjacent nitrogen atom to form a heterocyclic ring containing optionally substituted 5 or 6 membered nitrogen which optionally contains 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as the constituent atoms of the ring; the compound as in terms of a group represented by Xb, R2b is a hydrogen atom or an alkyl group of C? -, R3b is (1) a hydrocarbon group selected from (a) C? _7 alkyl, (b) C3- cycloalkyl, (c) C2-6 alkenyl, (d) C6-10 aryl and (e) C6-? or C- alkyl- [wherein (a) C alquilo _ alkyl, (b) C3_7 cycloalkyl, and (c) C 2-6 alkenyl can be substituted respectively with 1 to 4 substituents selected from (i) carboxyl group optionally esterified with C? _6 alkyl or C6-? alkyl or C? _4 alkyl, (ii) phosphate group optionally mono- or disubstituted with C? -6 alkyl or C2_7-alkanoyloxy-C? -6 alkyl, (ii) a sulfonate group, (iv) ) sulfonamide group optionally substituted with C? -6 alkyl or Ce-1-C? _4 alkyl aryl, (v) hydroxy group optionally alkylated with C? _3 alkyl, (vi) sulfhydryl group optionally alkylated with C-alkyl ? 3, (vii) a carbamoyl group, (viii) phenyl group optionally substituted with 1 to 5 substituents optionally selected from a hydroxy group, a chlorine atom, a fluorine atom, aminosulfonyl group and amino mono- or di-substituted with alkyl d e C? _3, (ix) amino group optionally mono- or disubstituted with C? -3 alkyl, (x) cyclic amino group derived from piperidine, pyrrolidine, tetrahydrooxazine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzylpiperazine, phenylpiperazine, 1, 2, 3, 4-tetrahydroisoquinoline or phthalimide which can be substituted with C3_3 alkyl, benzyl or phenyl and (xi) a 5-6 membered aromatic heterocyclic group derived from pyridine, imidazole, indole or tetrazole; Y (d) C6-? oy aryl (e) C6-? 0 -alkyl-C4 alkyl can be substituted respectively with 1 to 4 substituents selected from (i) carboxyl group optionally esterified with C? _4 alkyl, ( ii) phosphate group optionally mono- or disubstituted with C_6 alkyl or C2_7 alkanoyloxy-C6_6 alkyl, (iii) a sulfonate group, (iv) C ?_4 alkylsulfonyl group, Cß-io aryisulfonyl or C6 arylsulfonyl -? or -alkylsulfonyl of C? _4, (v) sulfonamide group optionally substituted with C? -6 alkyl or C6-? aryl or C? _4 alkyl, (vi) C? _3 alkyl group optionally substituted with group carboxyl optionally esterified with C? _4alkyl, phosphate group optionally mono- or disubstituted with C?-C alquilo alquiloalkyl, a sulfonate group, C? _4alkylsulfonyl, C ar-arylsulfonyl or C C_? 0-alkylsulfonyl aryl of C? -4, sulfonamide group optionally substituted with C6-6 alkyl or C6-x aryl or C4-4 alkyl and (vii) a halogen atom]. , (2) tetrazolyl group, 4,5-dihydro-5-oxo-l, 2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3 -oxo-l, 2, 4-oxadiazolyl, 2,3-dihydro-3-thioxo-l, 2,4-oxadiazolyl, 3,5-dioxo-l, 2,4-oxadiazolidinyl, 4,5-dihydro-5 -oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-l, 3, -oxadiazolyl, 2,3-dihydro-3-oxo-l, 2, 4- tetrazolyl or 2,3-dihydro-3-thioxo-1,2-tetrazolyl, or (3) an acyl group selected from (i) a group C2_7 alkanoyl which can be substituted with 1 to 2 halogen atoms, and (ii) a Cß-io arylsulfonyl group optionally substituted with 1 to 4 substituents selected from C?-3 alkyl, C?-3 alkoxy and a halogen atom, a C? -4 -4 alkylsulfonyl group or an aryl group of C6-? o_ alkylsulfonyl of C? _4, or R2b and R3 can be combined together with the adjacent nitrogen atom to form a 5- or 6-membered ring derived from piperidine, piperazine, pyrrolidine, 2-oxopiperazine, 2-6- dioxopiperazine, tetrahydrooxazine or thiomorpholine [wherein, the 5-membered or 6-membered ring is optionally substituted with 1 to 4 substituent selected from (A) hydroxy group optionally substituted with C? _3 alkyl or C2_7 alkanoyl, (B) carboxyl group optionally esterified with C? -6 alkyl or Cd-xalkyl C? _ alkyl, (C) phosphate group optionally substituted with mono- or dialkyl of C? _6 or C2-7 alkanoyloxy-C? _6 alkyl, (D) a sulfonate group, (E) sulfonamide group optionally substituted with C? _6 alkyl or C6-? O-alkyl aryl ilo of C? _, (F) C? -6 alkyl and C2-s alkenyl each of which may be optionally substituted with a carboxyl group optionally esterified with C? _6 alkyl or C6-? C? -4 alkyl; a phosphate group mono- or disubstituted with C? -6 alkyl or C2_7-alkanoyloxy-C? _6 alkyl, or a sulfonate group; sulfonamide group optionally substituted with C? _6 alkyl or Ce-x or C? _4 alkyl; a hydroxy group optionally substituted by C? -3 alkyl or C2_7 alkanoyl; a sulfhydryl group optionally alkylated with C? _3 alkyl; a carbamoyl group; phenyl optionally substituted with 1 to 5 substituents optionally selected from a hydroxy group, a halogen atom, an aminosulfonyl and an amino group substituted with C? _3 alkyl; an amino group optionally mono- or di-substituted with C? _3 alkyl; or tetrazolyl, (G) amino group optionally mono- or disubstituted with C? -3 alkyl, (H) a cyclic amino group derived from piperidine, pyrrolidine, tetrahydrooxazine, thiomorpholine, 4-methylpiperazine, 4-benzylpiperazine or 4-phenylpiperazine, (I) a cyano group, (J) a carbamoyl group, (K) an oxo group, (L) a tetrazolyl or 2,5-dihydro-5-oxo-l, 2,4-oxadiazolyl group, (M) group carbamoyl optionally substituted with C 1 -i arylsulfonyl. C.sub.4-4 alkylsulfonyl or C.sub.6-4.alkyl or C.sub.4-4 alkylsulfonyl, (N) sulfhydryl group optionally alkylated with C.sub.3 -C.sub.3 alkyl, and (O) phenyl group which can be substituted with 1 to 5 substituents selected from an hydroxy group, a halogen atom, aminosulfonyl group and amino optionally i substituted with C? -3] alkyl; the compound where in a group represented by b. R2b and R3 can be combined together with the nitrogen atom adjacent to the carbamoyl group to form a ring of 5 or 6 members derived from piperidine, piperazine, pyrrolidine, 2-oxopiperazine or 2,6-dioxopiperazine, and the 5- or 6-membered ring can be substituted with a C? _6 alkyl group having 1 to 2 optionally selected substituents of (i) carboxyl group optionally esterified with C? -6 alkyl or C6-? aryl or C? _4 alkyl, (ii) phosphate group optionally mono- or disubstituted with C? _6 alkyl or C2_7 alkanoyl-alkyl C? -6, (iii) a sulfonate group, (iv) sulfonamide group optionally substituted with C? _6 alkyl or C6-? Or C? _4 alkyl, (v) hydroxy group optionally alkylated with C? Alkyl? 3, (vi) sulfhydryl group optionally alkylated with C? _3 alkyl, (vii) a carbamoyl group, (viii) phenyl group which can be substituted with 1 to 5 substituents selected from a hydroxy group, a halogen atom, aminosulfonyl and amino optionally substituted by C ?3 alkyl, (ix) optionally mono amino group - or disubstituted with C? -3 alkyl, and (x) a tetrazolyl group; the compound wherein in a group represented by Xb, R 2b is a hydrogen atom or C alquilo _ alkyl, and R 3b is C? -4 -4 alkylsulfonyl; the compound wherein the heterocyclic group represented by Xb is tetrazolyl, 5-dihydro-5-oxo-l, 2, -oxadiazolyl, 4,5-dihydro-5-thioxo-1,2, -oxadiazolyl, 2,3- dihydro-3-oxo-l, 2, -oxadiazolyl, 2,3-dihydro-3-thioxo-l, 2, - oxadiazolyl, 3,5-dioxo-1,2,4-oxad? azolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-t? oxo-isoxazolyl, 2,3-d? hydro-2-oxo-l, 3,4-oxadiazolyl, 2,3-dihydro-3-oxo-l, 2,4-tetrazolyl or 2,3-dihydro-3-thioxo-1,2-tetrazolyl; the compound wherein R? b is methyl, W is a chlorine atom, Rb is branched C3_6 alkyl which is substituted with 1 to 3 substituents selected from a hydroxy, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy group and -aminoprop? onyloxy, and Xb is a group represented by the formula: where, R2b. represents a hydrogen atom or C? _7 alkyl and R3 'represents C? -4 alkyl; the compound wherein R? b is methyl, W is a chlorine atom, Rb is branched C3_6 alkyl which is substituted with 1 to 3 substituents selected from a hydroxy, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy group and 2-aminopropionyloxy, and Xb is a group represented by the formula: O / V -N \ (CH,) - N where, Rb. represents a hydrogen atom or C? -7 alkyl, and n represents an integer from 1 to 5; the compound wherein R? b is methyl, W is a chlorine atom, Rb is branched C3_6 alkyl which is substituted with 1 to 3 substituents selected from a hydroxy, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy group and -aminopropionyloxy, and Xb is a group represented by the formula: wherein, R "represents a hydrogen atom or C? -4 alkyl, the compound wherein Rlb is methyl, W is a chlorine atom, Rb is branched C3_6 alkyl which is substituted with 1 to 3 substituents selected from an hydroxy group, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and Xb is tetrazolyl, the compound wherein Rb is lower alkyl optionally substituted with 1 or 2 hydroxy groups, and Xb is (1) is carbamoyl group optionally substituted with a hydrocarbon group selected from (a) C? _7 alkyl, (b) C3-7 cycloalkyl, (c) C2_6 alkenyl, (d) C? -io aryl and (e) C7_? arylalkyl. [where, (a) alkyl of C? -7, (b) C3_7 cycloalkyl and (c) C2_6 alkenyl may have 1 to 4 substituents respectively selected from (i) carboxyl group optionally esterified with C6_6 alkyl or C7_6 arylalkyl, (ii) a phosphate group, (iii) a sulfonate group, (iv) sulfonamide group optionally substituted with C?-6 alkyl or C 7? 0 arylalkyl, (v) hydroxy group optionally alkylated with C?-3 alkyl, (vi) sulfhydryl group optionally alkylated with alkyl of C? _3, (vii) a carbamoyl group, (viii) a phenyl group optionally substituted with substituents optionally selected from a hydroxy group, a chlorine atom, a fluorine atom, aminosulfonyl and amino group mono- or disubstituted with C-alkyl ? 3, (ix) amino group optionally mono- or disubstituted with C? -3 alkyl, and (x) cyclic amino group derived from piperidine, pyrrolidine, tetrahydrooxazine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzylpiperazine, or -phenylpiperazine which can be substituted with alq C3_3, benzyl or phenyl, and (xi) 5- or 6-membered aromatic heterocyclic group derived from pyridine, imidazole, indole or tetrazole, and (d) C6-? oy and (e) arylalkyl of C7_? 4 can having 1 to 4 substituents respectively selected from (i) carboxyl group optionally esterified with C? - alkyl, (ii) a phosphate group, (iii) a sulfonate group, (iv) sulfonamide group optionally substituted with C? _6 alkyl or C7 arylalkyl?, (v) C? _3 alkyl group optionally substituted with carboxyl group which can be esterified with C? -4 alquilo alquiloalkyl, a phosphate group, a sulfonate group, or sulfonamide group optionally substituted with C?--alkyl or C ar-? ar arylalkyl, and (iv) an atom halogen], (2) tetrazolyl, 5-dihydro-5-oxo-l, 2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2, -oxadiazolyl, 2,3-dihydro-3 group -oxo-l, 2, -oxadiazolyl, 2,3-dihydro-3-thioxo-l, 2,4-oxadiazolyl, 3,5-dioxo-l, 2,4-oxadiazolidinyl, 4,5-dihydro-5- oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-l, 3,4-oxadiazolyl, 2,3-dihydro-3-oxo-l, 2, 4- tetrazolyl or 2,3-dihydro-3-thioxo-1,4,4-tetrazolyl, (3) carbamoyl group optionally substituted with an acyl group selected from (i) a C2_7 alkanoyl group optionally substituted with 1 to 2 halogen atoms, and (ii) a C6-? arylsulfonyl group or an alkylsulfonyl group of C? -4 or an arylalkysulfonyl group of C7-? 4 each of which can be substituted with 1 to 4 selected substituents C3-C3 alkyl, C3-3 alkoxy and halogen atom, or (4) a cyclic amino carbonyl group derived from piperidine, piperazine, pyrrolidine, 2-oxopiperazine, 2,6-dioxopiperazine, tetrahydrooxazine and thiomorpholine [in wherein, the cyclic amino carbonyl group may have 1 to 4 substituents selected from (A) a hydroxy group, (B) carboxyl group optionally esterified with C 1 -C alkyl. 4, (C) a phosphate group, (D) a sulfonate group, (E) sulfonamide group optionally substituted with C? _6 alkyl or C7-? 0 arylalkyl, (F) C? -3 alkyl or C2_5 alkenyl , each of which can be substituted with that indicated above (A), (B), (C), (D) or (E), (G) amino group optionally mono- or disubstituted with C? _3 alkyl, (H) a cyclic amino group derived from piperidine, pyrrolidine, tetrahydrooxazine, thiomorpholine, 4-methylpiperazine, 4-benzylpiperazine or 4-phenylpiperazine, (I) a cyano group, (J) a carbamoyl group, (K) oxo, (L) C) -3 alkoxy, (M) a heterocyclic group derived from tetrazolyl or 2,5-dihydro-5-oxo-1,2, -oxadiazolyl, and (N) is carbamoyl group optionally substituted with aryisulfonyl Ce-xo, C7 - alkylsulfonyl or arylalkysulfonyl of C7_? 4]; the compound wherein Rb is a 2,2-dimethyl-3-hydroxypropyl group; or the similar. In the above-mentioned formula, examples of the lower alkyl group represented by Rb include C?-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl. Among these, a C3-6 alkyl group is preferable, and a C4-5 alkyl group is more preferable. In particular, a branched C4-5 alkyl group such as isobutyl and neopentyl is preferable. Examples of the lower alkyl substituent represented by Rb include hydroxy group optionally substituted by C2-2 alkanoyl or C? _7 alkyl, and the like. Examples of these substituents include a hydroxy, acetyloxy, propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy group. One to three of these substituents may be present in their substitutable positions. Additionally, examples of the optionally substituted lower alkyl represented by Rb include 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2 -hydroxymethyl-2-methyl-propyl and 3-acetoxy-2-acetoxymethyl-2-methylpropyl. The optionally substituted carbamoyl group represented by Xb includes a group represented by the formula: Examples of the "optionally substituted hydrocarbon group" represented by R2b and R3b include an optionally substituted C7_7 linear or branched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1, 1- dimethylethyl, n-pentyl, 3-methylbutyl, 2- methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, neopentyl, hexyl, heptyl), an optionally substituted C3-7 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, etc.), an optionally substituted C2_6 straight or branched alkenyl group (e.g., vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1) -propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.), a optionally substituted aryl group of Cβ-xo (for example, phenyl and naphthyl group) and an optionally substituted C7-14 arylalkyl group (for example, benzyl, phenethyl and naphthylmethyl). Examples of the substituent of "optionally substituted C7-7 straight or branched alkyl group, optionally substituted C3.7 cycloalkyl group and optionally substituted C2-6 linear or branched alkenyl group" include a carboxyl group optionally esterified with an alkyl group of C ? -6 or aryl group of C6_? 0-C? -4 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, phenyl, benzyl, etc.), optionally mono- or di-substituted phosphate group with C_6 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl, etc.) or C2_7-alkanoyloxy-C6_6 alkyl such as acetyloxymethyl or pivaloyloxymethyl group, a sulfonate group, sulfonamide optionally substituted with C?-6 alkyl group or C 6? 0 -alkyl group C 1-4 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, etc.), hydroxy group and sulfhydryl group, each optionally alkylated with C? -3 alkyl group (e.g., methyl, ethyl, propyl, etc.), a carbamoyl group, phenyl group optionally substituted with 1 to 5 substituents [e.g., a hydroxy group] , chlorine, fluorine, an aminosulfonyl group or amino group optionally substituted with C? _3 alkyl group (eg, methyl, ethyl, propyl, etc.)], an amino group optionally mono- or disubstituted with C? _3 alkyl group (for example, methyl, ethyl, propyl, etc.), a cyclic amino group (for example, a cyclic amino group of or 6 members cyclic amine derivative such as piperidine, pyrrolidine, tetrahydrooxazine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzylpiperazine, 4-phenylpiperazine, 1, 2, 3, 4-tetrahydroisoquinoline and phthalimide, which can be substituted with a group C? -3 alkyl, benzyl, phenyl or the like, and optionally further contains an oxygen atom or a sulfur atom as a constituent atom of the ring) and an aromatic heterocyclic ring from 5 to 6 members containing 1 to 4 heteroatoms selected from the N, 0 and S (for example, pyridine, imidazole, indole, tetrazole, etc.). Additionally, examples of the substituent of C6-aryl group and C6-aryl group or C? _4 alkyl as? substituent of an optionally substituted amino group which comprises a carbamoyl group of the "optionally substituted carbamoyl group" represented by Xb includes carboxyl group optionally esterified with C? _4 alkyl group (methyl, ethyl, propyl, tert-butyl group, etc.) , phosphate group optionally mono- or disubstituted with C? -6 alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl) or C2_7 alkanoyloxy-alkyl C? _6 as a pivaloyloxymethyl group and acetyloxymethyl group, a sulphonate group, C? -4 alkylsulfonyl, C? -io arylsulphonyl or C-4-alkylarylsulfonyl aryl, sulfonamide group substituted with an alkyl group of C? 6 or an aryl group of C6-? O-C4-4 alkyl optionally (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, etc.) and carboxyl group optionally esterified with an alkyl group of C? _4, phosphate group optionally mono- or disubstituted with a g C6-6alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl and hexyl or C2-7 alkanoyloxy group C6 alkyl such as pivaloyloxymethyl group, C3_3 alkyl group (for example, methyl, ethyl, propyl and isopropyl) optionally substituted with a sulfonate group and sulfonamide group optionally substituted with C6_6 alkyl group or a group C6-C4 alkyl aryl, and a halogen atom (e.g., fluorine and chlorine), and the like. The "hydrocarbon group" may have 1 to 5 substituents in a substitutable position. The "optionally substituted heterocyclic group" represented by R 2b and R 3b may have 1 to 2 (preferably one) of the substituents such as oxo group and thioxo group, and preferably is a heterocyclic group having a hydrogen atom which may be deprotonated. Such a heterocyclic group is preferably a heterocyclic group containing 5 to 6 members and 1 to 4, preferably 2 to 3 heteroatoms selected from S, O and N. Specific examples include tetrazolyl, 4,5-dihydro-5-oxo-l, 2 , 4-oxadiazolyl, 5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-l, 2,4-oxadiazolyl, 2,3-dihydro-3-thioxo- 1, 2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3- dihydro-2-oxo-l, 3, -oxadiazol i lo, 2, 3-dihydro-3-oxo-1, 2,4-tetrazolilo and 2, 3-dihidro-3-thioxo-l, 2,4-tetrazolilo . Among these, the tetrazolyl group is preferable. The examples of the "acyl group" represented by R2b i I and R3b include an acyl group of carboxylic acid derived from the carboxylic acid (for example, acyl group of C2.7 carboxylic acid such as acetyl, propionyl, butyryl, benzoyl, etc.) and C6-? o arylsulfonyl group. alkylsulfonyl group of C? _4 and C6-? or C6-4 arylsulfonyl group each of which may have a substituent (eg methylsulfonyl, ethylsulfonyl, phenylsulfonyl, naphthylsulfonyl, phenylmethylsulfonyl, phenylethylsulfonyl, naphthylmethylsulfonyl, naphthylethylsulfonyl, etc.). ). The substituent of aryl, alkyl and arylalkysulfonyl group includes C? _3 alkyl (e.g., methyl, ethyl, propyl, etc.), C? _3 alkoxy (e.g., methoxy, ethoxy, ethoxy, etc.), a halogen atom (for example, chlorine, fluorine, bromine) and the like, and 1 to 4, preferably 1 to 2, thereof may be present in a substitutable position. The acyl group of carboxylic acid indicated may have 1 to 2 halogen atoms (eg, chlorine, fluorine, bromine) as a substituent. Examples of the cyclic amino group optionally substituted by C?-C3 alkyl, C2_7 alkanoyl or the like which are formed by combining R2b and R3b together with the nitrogen atom adjacent to the carbamoyl group include a 5 or 6 membered cyclic amine derivative group. such as piperazine, piperidine, pyrrolidine, piperazin-2-one, piperazine-2,6-dione, tetrahydrooxazine and thiomorpholine, and said amine The cyclic may also contain 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as the constitutive atom of the ring. > Such a cyclic amino group may have 1 to 4, preferably 1 to 2 substituents. Examples of substituents include hydroxy group optionally substituted by C ?_3 alkyl or C2_7 alkanoyl group, carboxyl group optionally esterified with C ?_4 alkyl group (methyl, ethyl, propyl, tert-butyl, etc.) and arylalkyl C7-10, phosphate group optionally mono- or di-substituted with C? -6 alkyl or C2-7 alkanoyloxy-C? _6 alkyl group (acetyloxymethyl group, pivaloyloxymethyl group), a sulfonate group, and sulfonamide group optionally substituted with alkyl C? -6 or aryl group of C6-? O_alkyl of C? _4 (for example, methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, benzyl, etc.), C? _6 alkyl and C2_5 alkenyl each of which can be substituted with "carboxyl group optionally esterified with C? -6 alkyl or Ce-1-C-alkyl aryl?", phosphate group optionally mono- or disubstituted with C? -6 alkyl or C2_7-alkanoyloxy group C? _6 alkyl (eg, acetyloxymethyl group, pivaloyloxymethyl group I, etc.), a group or sulfonate, sulfonamide group optionally substituted by C ?_6 alkyl or aryl group of C 6 - ω or C alquilo_alkyl, hydroxy group optionally substituted by C ?_3 alkyl or C 2_ alkanoyl group ? , sulfhydryl group optionally alkylated with C? _3 alkyl, a carbamoyl group, phenyl group optionally substituted with 1 to 5 substituents (for example, a hydroxy group, a halogen atom, aminosulfonyl, amino group optionally substituted with C? _3 alkyl, etc.), amino group optionally mono- or di-substituted with C?-3 alkyl group or tetrazolyl group ", amino group optionally mono- or di-substituted with C?-3 alkyl (e.g., methyl, ethyl, propyl, etc.), a cyclic amino group (a cyclic amine derivative group of 5 or 6 members which may contain additional heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom constitutive of the ring, and which may be substituted with C? -3 alkyl, benzyl, phenyl, or the like, for example, piperidine, pyrrolidine, tetrahydrooxazine, thiomorpholine, 4-methylpiperazine, 4-benzylpiperazine, 4-phenylpiperazine, or the like), a cyano group , a carbamoyl group, a group oxo, C? _3 alkoxy (eg, methoxy, ethoxy, ethylenedioxyl, etc.), heterocyclic group optionally substituted by an oxo or thioxo group having a hydrogen atom that can be deprotonated as previously stated (for example, tetrazolyl, 2,5-dihydro-5-oxo-l, 2,4-oxadiazolyl, etc.), Cß-io arylsulfonyl. Ce-io-alkylsulfonyl aryl of C? _4 and C? _4 alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, phenylsulfonyl, benzylsulfonyl, etc.) which is exemplified for the substituent of an optionally substituted amino group that makes up the carbamoyl of the "optionally substituted carbamoyl group" represented by X, sulfhydryl group optionally alkylated with alkyl of C? _3, or phenyl substituted carbamoyl group which can be substituted with 1 to 5 substituents (for example, a hydroxy group, a halogen atom, an aminosulfonyl and amino group optionally substituted with C? -3 alkyl). Examples of the optionally substituted carbamoyl group represented by Xb include: O, V R = b- and Rb 'include a hydrogen atom and C? _7 alkyl. The hydrogen atom is particularly preferable. The alkyl of C? _7 represented by R2b, R2b- and Rb. it includes the same groups as those exemplified with respect to the C 7 -7 alkyl mentioned above of the "hydrocarbon group." R "includes a hydrogen atom and C alquilo _ alkyl.The hydrogen atom is particularly preferable.C El ?4 alkyl represented by R 3b 'and R" includes, for example, methyl, ethyl, propyl, isopropyl, n- butyl, tert-butyl, etc. As for the optionally substituted heterocyclic group possessing a hydrogen atom which can be deprotonated represented by Xb, a 5- to 6-membered heterocyclic ring containing nitrogen (preferably containing 1 to 4 nitrogen atoms) having active proton such as Broensted acid is preferable, and those containing 1 to 4, preferably 2 to 3, of a nitrogen atom, a sulfur atom and an oxygen atom may be preferable. Substituents include an oxo group and a thioxo group thereof, and 1 to 2, preferably 1, of such substituents may be present. Examples of the "optionally substituted heterocyclic group possessing a hydrogen atom that can be deprotonated" represented by X are exemplified by those of the "optionally substituted heterocyclic group" such as the substituent of the "optionally substituted carbamoyl group" represented by X such as tetrazolyl , 2, 5-dihydro-5-oxo-l, 2,4-oxadiazole? Similary. Examples of the "lower alkyl group" represented by Rlb include a C?-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, hexyl and the like. Among these, the C? -3 alkyl group is preferable. In view of the pharmacological activity, the methyl group is particularly preferred as Rib- The examples of the "halogen atom" represented by I I W include chlorine, fluorine, bromine, iodine atoms. The chlorine atom is particularly preferred. Examples of salts of the compound represented by formula (Ib) include pharmacologically acceptable salts such as inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like; organic salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate and the like; metal salts such as sodium salt, potassium salt, calcium salt, aluminum salt and the like; and salts with a base such as triethylamine salt, guanidine salt, ammonium salt, hydrazine salt, quinine salt, cinchonine salt and the like. Additionally, hydrates as well as non-hydrates of compounds represented by formula (Ib) are included within the scope of the present invention. ! I The compound represented by the formula (Ib) and salts thereof contain asymmetric carbon atoms in positions 3 and 5, in the present trans isomer wherein the substituents wherein the substituents at positions 3 and 5 are directed in the opposite direction in relation to the plane of a 7-membered ring is preferable, and in particular, the isomer is preferred wherein the absolute configuration at position 3 is the configuration R and the absolute configuration at position 5 is the configuration S. Regarding the compounds represented by the formula (Ib) or salts thereof, the following compounds are specifically preferred. N-methanesulfonyl- [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-oxo-l, 2,3,5 -tetrahydro-4, 1-benzoxazepin-3-yl] acetamide, N-methanesulfonyl- [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2-hydroxymethyl) -2-methylpropyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide, N- [2- (pyrrolidin-1-yl) ethyl] - [(3R , 5S) -7-chloro-5- I (2,3-dimethoxyphenyl) -1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide, N- [2- (pyrrolidin-1-yl) ethyl] - [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) - 2-oxo- i 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide, N-methanesulfonyl- [(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro -5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide, N-methanesulfonyl- [(3R, 5S) -1- (3-Acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1, 2,3,5-tetrahydro-, l-benzoxazepin-3-yl ] acetamide, N- [[(3R, 5S) -l- (3-acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2 acid, 3, 5-tetrahydro-4, 1-benzoxazepin-3-yl] acetyl] piperidin-4-acetic acid, N- [[(3R, 5S) -1- (3-hydroxy-2, 2-dimethylpropyl) -7] -chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-acetic acid, N- [[( 3R, 5S) -1- (2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3 -yl] acetyl] piperidine-acetic acid, N- [[(3R, 5S) -1- (3-acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl)] -2- oxo-l, 2,3,5-tetrahydro-4, 1-benzoxazepin-3-yl] acetyl] piperidin-4-acetic, N - [[(3R, 5S) -1- (3-acetoxy-2,2 -dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidin-4-acetate ethyl, N- [[(3R, 5S) -1- (3-acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2, 3,5-tetrahydro-4, 1-benzoxazepin-3-yl] acetyl] piperidin-4-acetate ethyl, (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -1, 2, 3, 5-tetrahydro-3- [ 1H (or 3H) -tetrazole-! 5-yl] methyl-4, l-benzoxapin-2-one, (3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2-hydroxymethyl-2-methylpropyl) ) -1,2,3, 5-tetrahydro-3- [1H (or 3H) -tetrazol-5-yl] methyl-, l-benzoxazepin-2-one, (3R, 5S) -1- (3-acetoxy) -2, 2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -1, 2, 3, 5-tetrahydro-3- [1H (or 3H) -tetrazoi5-yl] methyl-4, l -benzoxazepin-2-one, (3R, 5S) -1- (3-acetoxy-2-acetoxymethyl-2-methylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -l, 2,3,5 -tetrahydro-3- [lH (or 3H) -tetrazol-5-yl] methyl-, l-benzoxazepin-2-one, N- [2- (pyrrolidin-l-yl) ethyl] - [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1-neopentyl-2-oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetamide, and the like. The compound represented by the formula (Ib) and salts thereof can be prepared according to the methods described in the publications, for example, EP-A-567026, W095 / 21834 (a PCT application based on the Japanese patent application No 6-15531), EP-A-645377 (an application based on Japanese Patent Application No. 6-229159), EP-A-645378 (an application based on Japanese Patent Application No. 6-229160), WO97 / 10224 and the like, or methods similar thereto. i As the compound represented by the formula (I), the compound represented by the formula (le) indicated above: It is preferred. Preferable examples of the compound represented by the formula (le) include: the compound wherein Rlc is a 3-carboxypropyl group, a 1-carboxyethyl group, or a linear alkylsulfonyl group of C3_6, a (C5_ carboxycycloalkyl) -alkyl group of C? _3, a group (carboxifuryl) alkyl, an aryl group of C? -io carboxyl, an aryl group of C6-? Or (carboxyalkyl of C2-3) or a aralkyl group C7-? 4 (carboxyalkyl of C? _3) , each of which may be optionally substituted; the compound wherein Rlc is an aryl group of C6-? or (carboxyalkyl of C? -4) which may have a substituent; the compound wherein Rlc is an aryl group of Ce-xo (C2_3 carboxyalkyl) which may have a substituent; the compound wherein Rlc is a phenyl (C2-3 carboxyalkyl) group which may have a substituent; the compound wherein Rlc is a group (carboxifuryl) -alkyl which may have a substituent; the compound wherein R2c is a C3_6 alkyl group which may have an alkanoyloxy group and / or a hydroxy group; the compound wherein R2c is a C3_6 alkyl group which may have 1 to 3 substituents selected from the group hydroxy, acetoxy, propionyloxy, tert-butoxycarbonyloxy and palmitoyloxy; the compound wherein R2c is 2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl or 3-acetoxy-2,2-dimethylpropyl; the compound wherein R3c is methyl group; the compound wherein W is a chlorine atom; the compound that has configuration R in position 3, and configuration S in position 5; and the similar. In the formula indicated above, Rlc represents an optionally substituted 1-carboxyethyl group, an optionally substituted linear C3_6 carboxyalkyl group, an optionally substituted C3_6 linear alkylsulfonyl group, an optionally substituted C ?_3 (C5_7 carboxycycloalkyl) alkyl group, or a group that is represented by the formula -Xlc-X2c-Ar-X3c-Xc-COOH (wherein Xlc and Xc respectively represent a bond or an alkylene group of optionally substituted C? _, X2c and X3c respectively represent a bond, -O- or -S-, and Ar represents an optionally substituted bivalent aromatic ring group. With the proviso that, when Xlc is a link, X2c represents a link, and when X4c is a link, X3c represents a link). Examples of the linear C3_6 alkyl group in the optionally substituted C3_6 linear carboxyalkyl group represented by Rlc include n-propyl, n-butyl, n-pentyl, n-hexyl. Among these, n-propyl and n-butyl is preferable, and n-propyl is more preferable. Examples of the linear C3-6 alkyl group in the optionally substituted C_6 linear sulfonylalkyl group represented by Rlc include n-propyl, n-butyl, n-pentyl, n-hexyl. Among these, n-propyl and n-butyl is preferable, and n-propyl is more preferable. Examples of the cycloalkyl group of Cs-7 in the (C5_7 carboxycycloalkyl) -alkyl optionally substituted alkyl represented by Rlc include cyclopentyl, cyclohexyl and cycloheptyl. Among these, cyclopentyl and cyclohexyl are preferred, and cyclohexyl is more preferable. Examples of the C? -3 alkyl group in the (optionally substituted I IC C -3 carboxycycloalkyl) -alkyl group represented by R include methyl, ethyl, n-propyl and isopropyl. Among these, methyl and! 1 ethyl, and methyl is more preferable. In the group represented by the formula -Xlc-X2c-Ar-! X -X -COOH for R, examples of the "alkylene group of C? _ 4" in the optionally substituted C? _4 alkylene group "represented by Xlc and X4c include methylene, dimethylene, trimethylene, tetramethylene, and alkylene group is preferred of C? -3, and among them, the linear one may preferably be used Examples of the "bivalent aromatic ring group" in the "optionally substituted divalent aromatic ring group" represented by Ar include a bivalent aromatic hydrocarbon group, a bivalent aromatic heterocyclic group, and the like. Here, examples of the divalent aromatic hydrocarbon group include a group formed by removing a hydrogen atom from the C6-aryl group or (eg, phenyl, naphthyl, etc.), and phenylene is preferably used as an aromatic hydrocarbon group bivalent. Examples of the bivalent aromatic heterocyclic group include a group formed by removing a hydrogen atom from an aromatic heterocyclic group containing at least 1 (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) types of heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom as constituent atoms of the ring system (ring atom). In the present, the examples of the group aromatic heterocyclic include a 5-6 membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl (preferably, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl, etc.) and a fused aromatic heterocyclic group of 8 to 12 members such as benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, a-carbolinyl, ß-carbolinyl, ? -carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxyntinyl, thiantrenyl, phenatridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2- a] pyrimidinyl, 1,2,4-triazolo [4, 3-a] pyridyl and 1, 2, -triazolo [4, 3-b] pyridazinyl (preferably, a heterocyclic group in the I which aromatic monocyclic 5- to 6-membered heterocyclic group indicated above is fused to a benzene ring, or a heterocyclic group in which two identical or different aromatic monocyclic heterocyclic groups of 5 to 6 members as above are fused, and more preferably, a group heterocyclic in which the aromatic monocyclic 5- to 6-membered heterocyclic group indicated above is fused to a benzene ring). Examples of the substituent that can be possessed by the "alkylene group of C? _4" in the "optionally substituted C? _4 alkylene group" represented by Xlc and X4c; and the "bivalent aromatic ring group" in the "optionally substituted bivalent aromatic ring group" includes: (i) carboxyl group optionally esterified with an alkyl group of C? -6 or an aryl group of C? -io-C-alkyl ? -4 (eg, methyl, ethyl, propyl, isopropyl, butyl, tertbutyl, phenyl, benzyl, etc.), (ii) phosphate group optionally mono- or disubstituted with C? _6 alkyl (e.g., methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl, etc.) or C2_7 alkanoyloxy-C6-alkyl group such as acetoxymethyl and pivaloyloxymethyl, (iii) a sulfonate group, ( iv) sulfonamide group optionally substituted by an alkyl group of C? _6 or an aryl group of C6-? or -alkyl of C? _4 (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl, etc.), (v) hydroxy group and a sulfhydryl group each of which can be alkylated with an alkyl group of C? -3 (for example, methyl, ethyl, propyl, etc.), (vi) a carbamoyl group, (vii) phenyl group which can be substituted with 1 to 5 substituents [e.g. a hydroxy, chloro, fluoro, aminosulfonyl, and optionally substituted amino group with C? _3 alkyl group (for example methyl, ethyl, propyl, etc.)], and can be linked via 0 or S, (viii) optionally mono- or disubstituted amino group with an alkyl group of C? _3 (by example methyl, ethyl, propyl, etc.), (ix) cyclic amino group optionally substituted with 1 to 3 C? -3 alkyl groups (eg, methyl, ethyl, etc.), benzyl, phenyl and the like (eg example, a 5- to 6-membered cyclic amino group which may contain an oxygen atom or a sulfur atom as the constituent atoms of the ring in addition to a nitrogen atom. trógeno derived from the cyclic amino group (by elimination of a hydrogen atom) of a cyclic amine such as piperidine, pyrrolidine, tetrahydrooxazine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzylpiperazine, 4-phenylpiperazine, 1, 2, 3, - tetrahydroisoquinoline, phthalimide, etc.), (x) an aromatic 5- to 6-membered heterocyclic group which may contain 1 to 4 heteroatoms selected from N, O and S, and may be linked via O or S (e.g., pyridyl, imidazolyl, indolyl, tetrazolyl, etc.), (xi) a halogen atom (e.g., chlorine, fluorine, bromine, iodine, etc.), (xii) a C 1-4 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C1-4 alkoxy group (for example, methoxy, ethoxy, ethoxy, isoethoxy, butoxy, t-butoxy, etc.) or alkylthio group C? _4 (for example , methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, etc.) each of which can be substituted with a substituent selected from the group C4_4alkoxy, alkylthio group C4_4, carboxyl group and phenyl group, (xiii) a cycloalkyl group of C5-7 (for example, cyclopentyl, cyclohexyl, cycloheptyl, etc.), and (xiv) a C7-7 alkanoyloxy group (eg, formyloxy, acetoxy, propionyloxy, butyryloxy, t-butoxycarbonyloxy) , isobutyryloxy, valeryloxy, pivaloyloxy, etc.). From 1 to 6, preferably 1 to 3 of these substituents may be present in a substitutable position. Additionally, two substituents can be combined to form C3.6 alkylene, C3_6 alkyleneoxy, C3_6 alkylenedioxy or the like, for example, when two adjacent substituents are combined in a phenyl group to form C4 alkylene, tetrahydronaphthalene group is formed . Specific examples of the group represented by the formula -Xlc-X2c-Ar-X3c-X4c-COOH in Rlc include an optionally substituted (carboxyheteroaryl) -alkyl group of C [beta] -4 [preferably, a (carboxypuryl) -alkyl group of C. ?-4 optionally substituted], an optionally substituted C6- (C6-) carboxy (C6-yl) -alkyl group, an optionally substituted carboxyheteroaryl group, a C6-? or optionally substituted carboxiaryl group, a group (C? _4 carboxyalkyl) optionally substituted heteroaryl, a (C?-α) -aryl C6- [alpha] -aryl or optionally substituted (preferably a (C2-3 carboxyalkyl) -6- [alpha] -] aryl group, a (carboxyalkyl) group C? _4) optionally substituted heteroaryl C 1-4 alkyl, a (C 1-4 carboxyalkyl) -aralkyl optionally substituted C 1-4 alkyl group [preferably, a (C? -3) carboxyl alkyl-C 7 aralkyl? optionally substituted], a (C? _4 carboxyalkoxy) -6- or optionally substituted aryl group, a (C?-C) carboxyl-aryl-Cß-io-C--alkyl optionally substituted alkyl, a group (optionally substituted); optionally substituted C 1 -C 4 alkylaryl C 1-4 alkyloxycarboxylalkyl, optionally substituted C 1-4 -carboxaryloxy- group of C 4 -alkyl substituted and a (optionally substituted) C-4-carboxyalkylthio-heteroaryl group. In the present, the same group as the "aromatic heterocyclic group" indicated above can be exemplified by heteroaryl, and the heteroaryl can have the same substituent as the substituent of the "aromatic heterocyclic group" indicated above.

Additionally, examples of Cß-io aryl include phenyl, naphthyl, azulenyl, and phenyl is preferably used. The Cß-io aryl may have the same substituent as the substituent of the "aromatic heterocyclic group" indicated above may have. Examples of the alkyl group in the optionally substituted (carboxypuryl) -alkyl group of C4_4 represented by R1 include linear or branched C ?_4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1, 1-dimethylethyl, and the like. Among these, an alkyl group of Cl-4 such as methyl, ethyl, n-propyl, isopropyl and n-butyl is preferred, and methyl, ethyl and n-propyl are more preferable. Examples of the carboxifuryl group include 3-carboxy-2-furyl, 4-carboxy-2-furyl, 2-carboxy-3-furyl, 2-carboxy-5-furyl and the like. Among these, 3-carboxy-2-furyl and 4-carboxy-2-furyl are preferred, and 3-carboxy-2-furyl is more preferable. Examples of the C2_3 alkyl group in the (C2_3 carboxyalkyl)-optionally substituted C6-10 alkyl represented by Rlc include ethyl, n-propyl and isopropyl, and ethyl and n-propyl are preferable. Examples of the aryl group of C6-? Or include phenyl, naphthyl and azulenyl, and phenyl is preferable. Examples of the C? -3 alkyl group in the group (C? _3 carboxyalkyl) -aralkyl of C7_? 4 optionally substituted represented by Rlc include methyl, ethyl, n-propyl and isopropyl, and methyl and ethyl are preferred, and ethyl is particularly preferred. Examples of an aralkyl group of C7_? 4 (an aryl group of C? -io-C? -4 alkyl) include phenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, ( 1-naphthyl) methyl, (2-naphthyl) methyl, 1- (1-naphthyl) ethyl, 1- (2-naphthyl) ethyl, 3- (1-naphthyl) propyl, 3- (1-naphthyl) propyl, - (l-naphthyl) butyl and 4- (2-naphthyl) butyl, and phenylmethyl, 1-phenylethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl, (1-naphthyl) ethyl and is preferably (2-naphthyl) ethyl, and is particularly preferred phenylmethyl and 2-phenylethyl. As for the substituent in case of each group represented by Rlc having a substituent, it is the same as the substituent of the "bivalent aromatic ring group" in the "optionally substituted divalent aromatic ring group" represented by Ar can have and can to be exemplified by, and 1 to 6, preferably 1 to 3 of these substituents which may be present in substitutable positions. Additionally, in each group represented by Rlc, it is preferable that the carboxyl portion is not substituted, and an arbitrary portion other than the carboxyl portion may have a substitutable substituent in a substitutable position.

As to Rlc, 3-carboxypropyl group, 1-carboxyethyl group, or a linear C3_6 sulfonylalkyl group, a (C5_7 carboxycycloalkyl) -alkyl group, a (carboxyfuryl) -alkyl group, a C-carboxyaryl group -xo? a group (C4_4 carboxyalkyl) -6C6-aryl or [preferably, a (C2_3 carboxyalkyl) -Ci-ioaryl] group. and a (C?-3) carboxyalkyl-aralkyl group of C 7? 4 is preferred, each of which may have a substituent and the like, a (C?-C carbox-carboxy alkyl) -α-Car-aryl group is preferred. optionally substituted, and a (C2-3 carboxyalkyl) -aryl-optionally substituted aryl group is more preferable. In particular, an optionally substituted (C2-3 carboxyalkyl) -phenyl group is preferred. Examples of the C3-6 alkyl group in the C3_6 alkyl group optionally substituted with an alkanoyloxy group or a hydroxy group represented by R2c include n-propyl, isopropyl, 1,1-dimethylethyl, n-butyl, isobutyl, n-pentyl , 2, 2-dimethylpropyl, isopentyl, n-hexyl, isohexyl and the like. Among these, isopropyl, 1,1-dimethylethyl, n-butyl, isobutyl, 2,2-dimethylpropyl and isohexyl are preferred, and 2, 2-dimethylpropyl is particularly preferred. Examples of the alkanoyloxy group in the C3_6 alkyl group optionally substituted with an alkanoyloxy group or a hydroxy group represented by R2c include a C2_2o alkanoyloxy group such as formyloxy, acetoxy, propionyloxy, butyryloxy, tert-butoxycarbonyloxy, isobutyryloxy, valeryloxy, pivaloyloxy, lauryloxy, palmitoyloxy, stearoyloxy (preferably an alkanoyloxy group of C? _7, etc.). Among these, acetoxy, propionyloxy, tert-butoxycarbonyloxy and palmitoyloxy are preferred, and acetoxy is particularly preferred. From 1 to 3 alkanoyloxy groups or hydroxy groups can replace a substitutable position. Preferable examples of C3_6 alkyl group optionally substituted with an alkanoyloxy group or a hydroxy group represented by R2c include 2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-Acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl and 3-acetoxy-2-acetoxymethyl-2-methylpropyl. Among these, 2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl and 3-acetoxy-2,2-dimethylpropyl are particularly preferred. Additionally, as R2c, a C3-6 alkyl group having an alkanoyloxy group and / or hydroxy group is preferred. Examples of the lower alkyl group represented by R3c include a C6_6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertbutyl, pentyl, hexyl. Among these, an alkyl group of C? _3 is preferred. In view of the pharmacological activity, particularly preferred the methyl group as R3c. Examples of the halogen atom represented by W include chlorine atom, fluorine, bromine and iodine. Among these, the chlorine atom is preferred. The present invention includes the compound represented by the formula (le) in the free form or a pharmacologically acceptable salt thereof. As said salt, when the compound represented by the formula (le) has an acidic group such as carboxyl group, it can form a salt with an inorganic base (for example, alkali metals such as sodium and potassium, ferrous alkali metals such as calcium and magnesium, transition metals such as zinc, iron and copper, etc.) or an organic base (for example, organic amine such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N'-dibenzylethylenediamine , and basic amino acids such as arginine, lysine and ornithine, etc.). In the case where the compound represented by the formula (le) of the present invention has a basic group such as the amino group, it can form a salt with inorganic acids or organic acids (for example, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, acid fumaric, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), and acidic amino acid such as aspartic acid, glutamic acid, and the like. The compound represented by the formula (le) or a salt thereof has asymmetric carbon atoms at positions 3 and 5, but may be formed in a mixture of stereoisomers, and the isomers may also be separated by conventional means. The trans isomer wherein the substituents at positions 3 and 5 are directed in the opposite direction relative to the 7-membered ring plane is preferable, and in particular, the isomer wherein the absolute configuration at position 3 is configuration R and the absolute configuration at position 5 is the S configuration is preferred. Additionally, it may be a racemic compound or an optically active isomer. The optically active isomer can be separated from the racemic compound by a known optical resolution means. As the compound represented by the formula (le) of the present invention or a salt thereof, the following compounds are specifically preferred. N-propanesulfonyl- [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2,3,5 -tetrahydro-, l-benzoxazepin-3-yl] acetamide or a salt of the same; Acid (2R) -2- [[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2 -dimethylpropyl) -2-oxo-l, 2,3,5 -tetrahydro-4, l-benzoxazepin-3-yl] acetyl] aminopropionic acid or a salt thereof; 3- [3- [[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2, 2-dimethylpropyl) -2-oxo-l, 2, 3, 5 acid -tetrahydro-4, 1-benzoxazepin-3-yl] acetyl] aminophenyl] propionic acid or a salt thereof; 4- [[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethylpropyl) -2-oxo-l, 2,3,5-tetrahydro-4 acid , 1-benzoxazepin-3-yl] acetyl] aminobutanoic or a salt thereof; I i Carboxylic acid of trans-4- [[(3R, 5S) -1- (3-acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxy phenyl) -2-oxo-1, 2, 3, 5-tetrahydro-4, 1-benzoxazepin-3-yl] acetyl] -aminomethyl-1-hexamethylene or a salt thereof; Trans-4- [[(3R, 5S) -7-chloro-5- (2, 3-, I-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, l-benzoxazepin-3-yl] acetyl] -aminomethyl-1-cyclohexanecarboxylic acid or a salt thereof; 3- [3- [[[(3R, 5S) -1- (3-Acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-, 1-benzoxazepin-3-yl] acetyl] amino] -4-fluorophenyl] propionic acid or a salt thereof; 3- [3- [[[(3R, 5S) -7-chloro-5- (2,3-) acid] dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] acetyl] amino] -4-methylphenyl] propionic or a salt thereof; 3- [3- [[[(3R, 5S) -1- (3-Acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, 1-benzoxazepin-3-yl] acetyl] amino] -4-methylphenyl] propionic acid or a salt thereof; 3- [3- [[[(3R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, l-benzoxazepin-3-yl] acetyl] aminomethyl] phenyl] propionic acid or a salt thereof; 3- [3- [[[(3R, 5S) -l- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, l-benzoxazepin-3-yl] acetyl] aminomethyl] phenyl] propionic acid or a salt thereof; 3- [3- [[[(3R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, 1-benzoxazepin-3-yl] acetyl] amino] -4-methoxyphenyl] ropionic acid or a salt thereof; 2- [2- [[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, l-benzoxazepin-3-yl] acetyl] amino] ethyl] furan-3-carboxylic acid or a salt thereof; 3- [3- [[[(3R, 5S) -7-Chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5- tetrahydro-4, l-benzoxazepin-3-yl] acetyl] amino] -4-fluorophenyl] propionic acid or a salt thereof; 3- [3- [[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid, 3,5-tetrahydro-, 1-benzoxazepin-3-yl] acetyl] aminophenyl] propionic acid or a salt thereof; 4- [3- [[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-, 1-benzoxazepin-3-yl] acetyl] amino] -4-methoxyphenyl] butanoic acid or a salt thereof; 5- [3- [[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, l-benzoxazepin-3-yl] acetyl] amino] -4-methoxyphenyl] pentanoic acid or a salt thereof; 5- [3- [[[(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, 1-benzoxazepin-3-yl] acetyl] amino] -4-fluorophenyl] pentanoic acid or a salt thereof. The compound represented by the formula (le) indicated above or a salt thereof can be! i produced, for example, according to a method described in EP A 567,026, W095 / 21834 (international application based on I Japanese Patent Application No. 6-15531), EP A 645,377 i (application based on Japanese patent application No. 6-229159), EP A 645,378 (application based on application for Japanese Patent No. 6-229160), WO01 / 98282 (International Application based on Japanese Patent Application No. 2000-190253) and the like, or analogous methods thereto. As the raw materials of the compound represented by the formula (I) of the present invention, the same salts as those mentioned above may be used, but they are not particularly limited so long as they do not interfere with the reaction. The preferable example of each of the definitions in the compound represented by formula (II) is as follows. The substituent of the "optionally substituted benzene ring" represented by the ring A includes halogen (for example fluorine, chlorine, bromine, iodine), an optionally substituted lower alkyl group having 1 to 4 carbon atoms (for example methyl, ethyl, propyl, butyl, tert-butyl etc.), an optionally substituted lower alkoxy group having 1 to 4 carbon atoms (for example methoxy, ethoxy, ethoxy, isoethoxy, butoxy, tert-butoxy etc.), a hydroxy group, a nitro group and cyano. Ring A can have 1 to 3, preferably 1 to 2, of these substituents. Adjacent substituents of these substituents can be linked together to form a ring. The substituent of the optionally substituted lower alkyl group having 1 to 4 carbon atoms or optionally substituted lower alkoxy group having 1 to 4 carbon atoms includes halogen (for example fluorine, chlorine, bromine, iodine), and 1 to 3 substituents may be in optional substitutable positions. Ring A is preferably a benzene ring substituted with halogen atoms, etc., more preferably a benzene ring substituted with a chlorine atom. Ring A is preferably a benzene ring represented by the formula: wherein W represents a halogen atom (for example fluorine, chlorine, bromine, iodine) and among others, W is preferably a chlorine atom. The substituent of the "optionally substituted benzene ring" represented by ring B includes the same number of the same groups as those exemplified above as a substituent of the "optionally substituted benzene ring" represented by ring A. Ring B is preferably a ring of benzene substituted with a lower alkoxy group having 1 to 4 carbon atoms, and among others, preferably a benzene ring represented by the formula: wherein R2a and R2b independently represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms (for example methyl, ethyl, propyl, butyl etc.) and particularly preferably R2a and R2b are both methyl groups. The aromatic ring of the "optionally additionally substituted aromatic ring" represented by ring C includes an aromatic hydrocarbon ring and an aromatic heterocyclic ring. For example, the aromatic carbide ring includes a benzene ring, a naphthalene ring and the like, and a benzene ring is preferable. The aromatic heterocyclic ring (aromatic heterocyclic ring of the "optionally additionally substituted aromatic heterocyclic ring" represented by ring C) includes, for example, an aromatic heterocyclic ring containing at least one (preferably 1 to 4, more preferably 1 to 2) 1 to 3 types (preferably 1 or 2 types) of heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like I, as atoms that make up the ring system (ring atoms).

The aromatic heterocyclic ring includes a 5- to 6-membered monocyclic aromatic heterocyclic ring such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole , 1, 3, -oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3-thiadiazole, 1,2,3-triazole, 1,2-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like; fused aromatic heterocyclic rings of 8 to 12 members such as benzofuran, isobenzofuran, benzo [b] thiophene, indole, isoindole, lH-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, benzopyran, 1,2-benzisothiazole, lH -benzotriazole, qumoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, diphenyleneimine, a-carboline, β-carboline, β-carboline, dibenzopyridine, phenoxazine, phenothiazine, phenazine, phenoxathine, thiantrene, phenanthridine, phenanthroline , indolizine, pyrrolo [1, 2-b] pyridazine, pyrazolo [1,5-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,5-ajpyridine, imidazo [1,2-b] pyridazine , imidazo [1,2-a] pyrimidine, 1, 2,4-triazolo [4, 3-a] pyridine, 1,2,4-triazolo [, 3-b] pyridazine and the like (preferably a heterocyclic ring in which the 5- to 6-membered monocyclic aromatic heterocyclic ring indicated above is fused with a benzene ring, or a heterocyclic ring in which two of the rings monocyclic aromatic heterocycles identical or different from 5 to 6 members indicated above are fused, more preferably a heterocyclic ring in which the 5- to 6-membered monocyclic aromatic heterocyclic ring indicated above is fused to a benzene ring) and the like. Ring C is preferably a monocyclic aromatic heterocyclic ring, a benzene ring or the like, and among others, a 5-membered monocyclic aromatic heterocyclic ring such as pyrazole, imidazole, thiazole, oxazole, isoxazole, 1, 2, 4 is preferable. -oxadiazole, 1, 3, 4-oxadiazole or the like. Although the ring C can be an aromatic ring possessing a hydrogen atom that can be deprotonated or an aromatic ring that does not have any hydrogen atom that can be deprotonated, an aromatic ring is preferred that does not have any hydrogen atom that can be deprotonated. The aromatic ring that does not have any hydrogen atom that can be deprotonated includes, in addition to an aromatic ring that originally has no hydrogen atom that can be deprotonated (for example benzene ring, thiazole, oxazole, isoxazole, 1, 2, 4-oxadiazole, 1,3,4-oxadiazole etc.), an aromatic ring in which a hydrogen atom is substituted which can be deprotonated (for example pyrrole, pyrazole, imidazole etc.) whose hydrogen atoms in the constituent nitrogen atom of the ring is substituted or which is linked to Xla or / and Xlb by the nitrogen atom constituting the ring). The substituent, whose aromatic ring of the "optionally additionally substituted aromatic ring" represented by the C ring can have, including (i) a carboxyl group optionally esterified with an optionally halogenated Cl-6 alkyl group or an aryl group of C6-? optionally halogenated C 4 alkyl (for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, phenyl, benzyl etc.), (ii) a phosphoric acid group optionally mono- or disubstituted with C alkyl? Optionally halogenated (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, hexyl etc.) or C2-7 alkanoyloxy-C6-6 alkyl such as acetoxymethyl or pivaloyloxymethyl, (iii) a sulfonic acid group, (iv) a sulfonamide group optionally substituted with an optionally halogenated C ?_6 alkyl group or an optionally halogenated C6-?? or C? -4 aryl group (eg methyl, ethyl) , propyl, isopropyl, butyl, ter-bu lime, benzyl etc.), (v) a hydroxy group and a sulfhydryl group which may be optionally substituted with an optionally halogenated C? _3 alkyl group (eg methyl, ethyl, propyl etc.), (vi) a carbamoyl group , (vii) a phenyl group optionally substituted with 1 to 5 substituents [e.g. hydroxy, chloro, fluoro, aminosulfonyl, amino group optionally substituted with C3_3 alkyl group (e.g. methyl, ethyl, propyl etc.)] and optionally limited to the aromatic ring by 0 or S, (viii) an amino group optionally mono- or disubstituted with an optionally halogenated C? -3 alkyl group (for example methyl, ethyl, propyl etc.), (ix) a cyclic amino group optionally substituted with 1 to C3_3 alkyl (for example methyl, ethyl etc.), benzyl, phenyl and the like (for example a 5- to 6-membered cyclic amino group optionally containing an oxygen atom or a sulfur atom in addition to the nitrogen atoms as the constituent atoms of the ring, as a cyclic amino group derivative (by elimination of a hydrogen atom) of the cyclic amine such as piperidine, pyrrolidine, tetrahydrooxazine, thiomorpholine, piperazine, 4-methylpiperazine, 4-benzyl lpiperazine, 4-phenylpiperazine, 1,2,3,4-tetrahydroisoquinoline or phthalimide), (x) an aromatic heterocyclic group of 5 to 6 members containing 1 to 4 heteroatoms selected from N, O and S and optionally limited to the aromatic ring by O or S (for example pyridyl, imidazolyl, indolyl, tetrazolyl etc.), (xi) a halogen atom (for example chlorine, fluorine, bromine, iodine etc.), (xii) an alkyl group of C? _4 (for example example methyl, ethyl, II propyl, isopropyl, butyl, tert-butyl, etc.), a C 1-4 alkoxy group (for example methoxy, ethoxy, ethoxy, isoethoxy, butoxy, tert-butoxy etc.) or an alkylthio group C? _4 ( for example methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, etc.) each of which can be optionally substituted with a substituent selected from a halogen atom, an alkoxy group of C? _4, an alkylthio group of C? 4, carboxyl and phenyl, (xiii) a C5_7 cycloalkyl group (for example cyclopentyl, cyclohexyl, cycloheptyl etc.), and (xiv) optionally halogenated C?-7 alkanoyloxy group (for example formyloxy, acetoxy, propionyloxy, butyryloxy, ter) -butoxycarbonyloxy, isobutyryloxy, valeryloxy, pivaloyloxy etc.). The "optionally additionally substituted aromatic ring" can be substituted with 1 to 6, preferably 1 to 3, of such substituents in the substitutable positions. Two such substituents can be linked together to form C3_6 alkylene, C3_6 alkyleneoxy C3_6 alkylenedioxy or the like. For example, when two adjacent substituents on a phenyl group are linked together to form C 4 alkylene, a tetrahydronaphthyl group is formed. The lower alkyl group of the "optionally substituted lower alkyl group" with an "optionally substituted hydroxy group" represented by R 1 includes, for example, C ?_6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , n-pentyl, isopentyl, neopentyl, hexyl and the like. Among them, an alkyl group of C3_6 is preferred and an alkyl group of C5 is more preferable. Among others, a branched C4_5 alkyl group such as isobutyl, neopentyl or the like is preferred. The substituent, of which the lower alkyl group of the "lower alkyl group optionally substituted by an optionally substituted hydroxy group" represented by R 1 may have, inclusive, a hydroxy group optionally substituted by C 2 -2 alkanoyl or C 1 7 alkyl. For example, such a substituent includes a hydroxy, acetyloxy (acetoxy), propionyloxy, tert-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy, 2-aminopropionyloxy group and the like. The lower alkyl group can be substituted with 1-3 of such substituents in substitutable positions. Examples of R1 include 1-propyl, 1-isopropyl, 1-isobutyl, 1-neopentyl, 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2, 2 -dimethylpropylo, 3-acetoxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2-acetoxymethyl-2-methylpropyl, [1- (hydroxymethyl) cyclobutyl] methyl and the like. Among these, 2, 2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl are preferable. , 3-acetoxy-2-acetoxymethyl-2-methylpropyl and the like. The lower alkylene of "lower alkylene optionally substituted "represented by Xla includes, for example, C? -6 alkylene such as methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, and the like, among which, the alkylene of! C? -4 is preferable. linear chain such as methylene, dimethylene, trimethylene, tetramethylene or the like, and more preferably the straight chain C? _3 alkylene.

The substituent, whose lower alkylene "Optionally substituted lower alkylene" represented by Xla may have, inclusive, the same groups as those exemplified above as substituents that the aromatic ring of the "optionally substituted additionally aromatic ring I" represented by ring C, may have; ! oxo group and the like. The "lower alkylene" can be substituted with 1 to 6, preferably 1 to 3, of such substituents in substitutable positions.

Xla is preferably a straight chain C? _3 alkylene bond or alkylene, and particularly preferably methylene. The lower alkylene of the "lower alkylene, optionally substituted" represented by Xlb includes the > same groups as those exemplified as the lower alkylene of the "optionally substituted lower alkylene" 'i represented by Xla. The substituents of the lower alkylene i 1 of the "optionally substituted lower alkylene" j 'represented by Xlb may have even the same number. of the same groups as those exemplified as a substituent that the lower alkylene of the "optionally substituted lower alkylene" represented X.sub.b is preferably a straight chain C? -3 bond or alkylene, and particularly preferably a bond. X2 is preferably a bond. The "bivalent hydrocarbon group" of the "optionally substituted divalent hydrocarbon group" represented by X3 includes a group formed by removing a hydrogen atom from a hydrocarbon group. The hydrocarbon group includes a straight or branched chain C?-7 alkyl group (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 2-ethylbutyl., 1-ethylbutyl, neopentyl, hexyl, heptyl), a C3_7 cycloalkyl group ( cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl etc.), a straight or branched chain C2_6 alkenyl group (for example vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, -methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl , 3-pentenyl, 4-pentenyl, I 1 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.), an aryl group of C6-? O (for example phenyl, naphthyl), arylalkyl group of C7-14 (for example benzyl, phenethyl, naphthylmethyl) and the like. The substituent, whose "bivalent hydrocarbon group" of the "optionally substituted divalent hydrocarbon group" represented by X3, may have even the same groups as those exemplified above as substituents that the lower alkylene of the "optionally substituted lower alkylene" may have. represented by Xla, optionally halogenated C? -6 alkylidene (for example methylidene, ethylidene, propylidene, isopropylidene, butenylidene etc.), vinylidene, cyclohexylidene, benzylidene and the like. The "bivalent hydrocarbon group" can be substituted with 1 to 6, preferably 1 to 3, of such substituents in the substitutable positions. The "bivalent hydrocarbon group" of the "optionally substituted bivalent hydrocarbon group" preferably represented by X3 includes (1) straight or branched chain alkylene in which the number of carbon atoms constituting the straight chain part is from 1 to 7 ( preferably 1 to 4) (for example methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, propylene, ethylmethylene, ethylethylene, propylethylene, butylethylene, methyltetramethylene, methyltrimethylene etc.), (2) a hydrocarbon chain containing a double bond in which the number of carbon atoms constituting the part of the linear chain is from 2 to 7 (preferably 2 to 4) (for example vinylene, propenylene, butenylene, butadienylene, methylpropenylene, ethylpropenylene, propylpropenylene, methylbutenylene, ethylbutenylene, propylbutenylene, methylbutadienylene, ethylbutadienylene, propylbutadienylene, pentenylene, hexenylene, heptenylene, pentadienylene, hexadienylene, heptadienylene, etc.), (3) phenylene (for example 1,2 phenylene, 1,3-phenylene, 1,4-phenylene etc.) and (4) a bivalent group in which phenylene and alkylene and / or alkenylene are combined (for example -CH2-CeH4-, -CH2CH2-CeH4- , -CH2-C6H4-CH2- etc.). X3 is preferably C4-4 alkylene such as methylene, ethylene, trimethylene, tetramethylene or the like, vinylene, propenylene, phenylene or the like. The "optionally esterified or amidated carboxyl group" represented by Y includes carboxyl, lower alkoxycarbonyl having 2 to 7 carbon atoms (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, etc.), aryloxycarbonyl of C7-? 4 (for example phenoxycarbonyl, 1- naphthoxycarbonyl), C 1 - 2 aralkyloxycarbonyl (for example benzyloxycarbonyl etc.), carbamoyl, N-alkylcarbamoyl of C?-6, N, N-dialkylcarbamoyl of C ?6, N-aralkylcarbamoyl of Cs- 2 2, N, N -diachalquilcarbamoyl of Cs-? 2, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl and the like. Among them, Y is preferable carboxyl, methoxycarbonyl, ethoxycarbonyl or the like, and carboxyl is particularly preferable. The compound represented by the formula (II) may be in a free form or in a pharmacologically acceptable salt form, and both forms are included within the scope of the present invention. When the compound represented by the formula (II) has an acid group such as a carboxyl group, etc., the compound can form a salt with inorganic bases (for example alkali metal such as sodium, potassium etc., alkaline earth metal such as calcium , magnesium etc., transition metal such as zinc, iron, copper etc.) or organic bases (for example organic amine such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and t-butylamine, basic amino acids such as arginine, lysine, ornithine, and the like). When the compound represented by the formula (II) of the present invention possesses a basic group such as an amino group or the like, the compound can form a salt with inorganic acids or organic acids (for example hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) or acidic amino acids such as aspartic acid or glutamic acid. The compound represented by the formula (II) or a salt thereof has asymmetric carbon atoms in the 3-position and the 5-position, and may be a mixture of stereoisomers. The isomers can be separated by known means. The preferred one is the trans form in which the substituents in the 3-position and the 5-position are directed in the opposite direction to each other in relation to each other in relation to the plane of the 7-membered ring, and specifically a compound possessing the absolute configuration represented by the formula (lia). Additionally, the compound represented by the formula (II) or a salt thereof may be in a racemic form or an optically active form, and the optically active form may be separated from the racemic form by resolution means. known optics. As the compounds represented by the formula (II) of the present invention or a salt thereof, the following are specifically preferred. (1) the compound wherein Xlb is a bond and Y is an optionally esterified carboxyl group; (2) the compound wherein ring A is a benzene ring substituted with halogen atom (s); (3) the compound wherein ring B is a benzene ring substituted with lower alkoxy group (s); (4) the compound wherein the C ring is an optionally additionally substituted monocyclic aromatic heterocyclic ring; (5) the compound wherein the C ring is an optionally further substituted benzene ring; (6) the compound wherein ring C is an optionally additionally substituted aromatic ring having no hydrogen atom that can be deprotonated; (7) the compound wherein Xla is alkylene of C? _3; (8) the compound wherein X2 is a bond; (9) the compound wherein X 3 is C 4 alkylene; (10) The compound wherein the formula (II) is the formula (lia): wherein the respective symbols are the same as those defined in formula (II); (11) 3- (2- { 3- [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2 acid -oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] propyl.] -1, 3-thiazol-5-yl) propionic acid, 3- (2-. {2 - [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethylpropyl) -2-oxo-l, 2,3,5-tetrahydro-4, 1- benzoxazepin-3-yl] ethyl.} - l, 3-thiazol-4-yl) propionic acid, or a salt thereof; (12) Acid (2- { [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-1 , 2,3,5-tetrahydro-4, 1-benzoxazepin-3-yl] methyl.}. - 1, 3-oxazol-5-yl) propionic acid, (2 { [(3R, 5S) - 7-Chloro-5- (2,3-dimethoxyphenyl) -1-isobuty1-2-oxo-1, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] methyl.} -1, 3 -oxazol-5-yl) acetic acid, or a salt thereof; (13) 5- (3 { [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethylpropyl) -2-oxo-l, 2 acid , 3,5-tetrahydro-4, 1-benzoxazepin-3-yl] methyl.}. -l, 2, -oxadiazole-5- il) pentanoic acid, 5- (3 { [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2 -oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] methyl.}. -l, 2, -oxadiazol-5-yl) pentanoic acid, 5- (3-. [(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4 , l-benzoxazepin-3-yl] methyl.} - L, 2,4-oxadiazol-5-yl) pentanoic acid, 4- acid. { [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2, 3, 5-tetrahydro-4 , l-benzoxazepin-3-yl] acetyl} phenyl) acetic, or a salt thereof; The compounds reented by the formula (II) can be produced by means of a method described in, for example, WO 2005/012272. Among the squalene synthase inhibitors indicated above, the following are particularly erable: (1) N- [[(3R, 5S) -l- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- ( 2, 3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] acetyl] piperidin-4-acetic, (2) 3- (2-. 3- [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2,3,5- tetrahydro-4, l-benzoxazepin-3-yl] propyl.] - l, 3-thiazol-5-yl) propionic acid, (3) 3- (2-. {2- (3R, 5S) - 7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethylpropyl) -2-oxo-l, 2,3,5- tetrahydro-4, l-benzoxazepin-3-yl] ethyl} -l, 3-thiazol-4-yl) propionic, (4) (2 { [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (3-hydroxy) -2, 2-dimethylpropyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] methyl.} -1, 3-oxa-zol-5-yl) propionic (5) (2- {[[3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -l-isobutyl-2-oxo-1,2,3,5-tetrahydro- 4, 1-benzoxazepin-3-yl] methyl.} -1, 3-oxazol-5-yl) acetic acid, (6) 5- (3 { [(3R, 5S) -7-chloro- 5- (2,3-dimethoxyphenyl) -1- (3-hydroxy-2, 2-dimethylpropyl) -2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] methyl} -1, 2, -oxadiazol-5-yl) pentanoic, (7) 5- (3 { [(3R, 5S) -1- (3-acetoxy-2, 2-dimethylpropyl) -7 acid -chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4, 1-benzoxazepin-3-yl] methyl.} -1, 2, -oxadiazole-5 -yl) pentanoic, (8) 5- (3 { [(3R, 5S) -7-chloro-5- (2,3-dimethoxyphenyl) -1- (2,2-dimethylpropyl) - 2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] methyl.} -1, 2, -oxadiazol-5-yl) pentanoic, and (9) acid do (4- { [(3R, 5S) -7-chloro-5- (2,3-dimethoxy phenyl) -1- (3-hydroxy-2,2 -dimethylpropyl) -2-oxo-l, 2,3,5-tetrahydro- , l-benzoxazepin-3-yl] acetyl} phenyl) acetic. The present invention can be realized with the following forms of administration. The mode of administration of a combination of a squalene synthase inhibitor (SSI) and an HMG-CoA reductase inhibitor (administration in combination) is not particularly limited, provided that the SSI and the HMG-CoA reductase inhibitor are in combination at the time of administration. Examples of such administration mode include: (1) the administration of a single preparation obtained by simultaneously formulating the SSI and the inhibitor of HMG-CoA reductase; (2) the simultaneous administration by the same route of administration of two types of preparations obtained by respectively formulating the SSI and the HMG-CoA reductase inhibitor; (3) the administration separated at an interval by means of the same route of administration of two types of preparations obtained by formulating the SSI and the HMG-CoA reductase inhibitor; (4) the simultaneous administration by means of a different route of two types of preparations obtained by respectively formulating the SSI and the HMG-CoA reductase inhibitor; (5) administration separated by an interval by means of a different route of administration of two types of preparations obtained by respectively formulating the SSI and the HMG-CoA reductase inhibitor (eg, administration of SSI and then the HMG-CoA reductase inhibitor in subsequent order or in reverse order). The dosage of the HMG-CoA reductase inhibitor can be appropriately selected based on the dosage used clinically. The combination ratio of the SSI and the HMG-CoA reductase inhibitor can be appropriately selected depending on the subject to be administered, route of administration, target disease, symptoms, combinations thereof or the like. For example, if the subject to be administered is a human being, although it depends on the types of HMG-CoA reductase inhibitor to be used, SSI may be used in an amount of 0.1 to 100 parts by weight (preferably, 0.5 to 100). parts by weight) (in the case of using atorvastatin as the inhibitor of HMG-CoA reductase, the SSI in an amount of 0.1 to 10 parts by weight, more preferably 0.5 to 10 parts by weight) based on 1 part by weight of the inhibitor of HMG-CoA reductase. When the above-mentioned invention is carried out, a pharmaceutical composition can be administered in a preparation form which is carried out by a conventional method using conventional carriers for formulation in adequate quantity, such carriers are appropriately selected, for example, from an excipient (eg, calcium carbonate, kaolin, sodium hydrocarbonate, lactose, starches, cellulose, crystalline, talc, crystallized sugar, porous substances, etc.), a binder (e.g., dextrin, gums, alcoholate, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, swarm, etc.), I decay agent (e.g., calcium carboxymethylcellulose, sodium croscaramellose, crospovidone, substituted hydroxypropylcellulose, partially starch) pregelatinized, etc.), lubricant (eg, magnesium stearate, calcium stearate, talc, starch, sodium benzoate, etc.), a colorant (eg, tar dye, caramel, ferric sesquioxide, titanium oxide , >; riboflavin, etc.), taste masking agent (for example, sweeteners, flavors, etc.), a stabilizer (for example, sodium sulfite, etc.), a preservative (for example, parabens, sorbic acid, etc.) and the like. The pharmaceutical preparations of the present invention comprising those indicated above contain SSI and / or HMG-CoA reductase inhibitor in an amount effective for the treatment and prevention of the disease. Additionally, the preparations used in the present invention may contain other ingredients of the drug such as! active ingredients such as SSI and / or HMG-CoA reductase inhibitor. Such ingredients are not limited ' particularly so long as the object of the present invention is achieved, and can be used in a convenient mixing ratio. Specific examples of preparation include tablets (including sugar-coated tablets, film-coated tablets, layered tablets), pills, capsules, granules, fine granules, powders, syrup, emulsion, suspension, injection, suspension for injection, inhaler, ointment , and the similar. These preparations may be a controlled release preparation (e.g., sustained release microcapsules) as fast release preparations and prolonged release preparations. Among these preparations, oral preparations which have advantages in convenience or complacency in some cases are preferred. When these preparations are a solid preparation, marks or characters can be printed for distinction therein or a slit line for division can be added. These preparations are prepared by a conventional method (for example, a method described in the Pharmacopoeia of Japan). In the practice of the present invention, when a solid preparation (called a fixed dose combination) containing both SSI ingredients and the HMG-CoA reductase inhibitor is used, it is produced, for example, according to the production method following . 1) after an SSI and an HMG-CoA reductase inhibitor are mixed together with additives such as excipients, the mixture is granulated while being sprayed with a dispersion or solution of additives such as binders in a solvent (eg water). The resulting granules are mixed with additives such as disintegrators and lubricants and then, if necessary, compressed to produce a solid preparation. 2) after an SSI is mixed with additives such as excipients, the mixture is granulated while being sprayed with a dispersion or solution of a HMGCoA reductase inhibitor, and additives such as binders in a solvent (eg water). The resulting granules are mixed with additives such as disintegrators and lubricants and then, if necessary, compressed to produce a solid preparation. I 3) after an SSI is mixed with additives such as excipients, the mixture is granulated while being sprayed with a dispersion or solution of additives such as binders in a solvent (for example water). On the other hand, after an HMG-CoA reductase inhibitor is mixed with additives such as excipients, the mixture is granulated while being sprayed with a dispersion or solution and additives such as binders in a solvent! (for example water). The granules containing SSI and the granules containing the HMG-CoA reductase inhibitor thus obtained are mixed together with additives such as disintegrators and lubricants and then, if necessary, tablets to produce a solid preparation. 4) after an SSI is mixed with additives such as excipients, the mixture is granulated while being sprayed with a dispersion or solution of additives such as binders in a solvent (for example water). On the other hand, additives such as excipients are sprayed to granulate with a dispersion or solution of an HMG-CoA reductase inhibitor, and additives such as binders in a solvent (for example water). The granules containing SSI and the granules containing the HMG-CoA reductase inhibitor thus obtained are mixed together with the additives such as disintegrators and lubricants and then, if necessary, compressed to produce a solid preparation. 5) after an SSI is mixed with additives such as excipients, the mixture is granulated while being sprayed with a dispersion or solution of additives such as binders in a solvent (eg water). The resulting granules are mixed with additives such as disintegrators and lubricants to obtain powder mixture.

On the other hand, additives such as excipients are sprayed to granulate with a dispersion or solution of an HMG-CoA reductase inhibitor, and additives such as binders in a solvent (for example water). The resulting granules are mixed with additives such as disintegrators and lubricants to obtain the powder mixture. The powder mixture containing SSI and powder mixture containing the HMG-CoA reductase inhibitor thus obtained are layered and then compressed to produce a solid preparation (two layer tablet). 6) after an SSI is mixed with additives such as excipients, the mixture is granulated while being sprayed with a dispersion or solution of additives such as binders in a solvent (for example water). The resulting granules are mixed with additives such as disintegrators and lubricants and then compressed into a tablet core. On the other hand, additives such as excipients are sprayed to granulate with a dispersion or solution of an HMG-CoA reductase inhibitor, and additives such as binders in a solvent (for example water). The resulting granules are mixed with additives such as disintegrators and lubricants to obtain a powder mixture.

The powder mixtures thus obtained are compressed as an outer layer in the tablet core described i I above to produce a solid preparation (dry coating tablet). 7) after an SSI is mixed with additives such as excipients, the mixture is granulated while being sprayed with a dispersion or solution of additives such as binders in a solvent (eg water). The resulting granules are mixed with additives such as disintegrators and lubricants and then compressed into a tablet. This tablet is coated with a HMG-CoA reductase inhibitor film solution, a base coat and additives such as light blocking agents to produce a solid preparation (film coated tablet). The dosage of the preparation of the present invention varies depending on the route of administration, symptoms and age or weight of patients, or the like. In the case of oral administration to an adult patient, it is preferable to administer 1 to 100 mg / day once as SSI or HMG-CoA reductase inhibitor or in two or more divided portions. The route of administration can be oral or non-oral. Examples Next, the excellent effects of the use in combination of Compound X will be explained. as the representative compound of SSI and some of the HMG-CoA reductase inhibitors when describing the specific pharmacological test results. However, these are examples of the combination effects of SSI and the HMG-CoA reductase inhibitor of the present invention, and thus this combinatorial effect is not limited to the following pharmacological effects. Example 1: Decreased effect on triglycerides in plasma using the combination of Compound X and atorvastatin. Test method: Wistar rats fat (female 19 weeks of age, N = 6), 10-ml / kg vehicle dose, Compound X (30 mg / kg) alone, atorvastatin (30 mg / kg) alone or the combination of both drugs was administered orally for 8 days, once a day. On the morning of the next day after administration 8, the blood was collected under fasting for one night, and the concentration of triglyceride in the plasma was measured. Result of the test: Combination of 142.9 ± 15.3 atorvastatin (30 mg / kg) + Compound X (30 mg / kg) Average + typical error (N = 6) Conclusion: By the use of the combination of Compound X and atorvastatin, an additional action of plasma triglyceride reduction was observed (P <0.01, bidirectional ANOVA method). Example 2: Effect of reduction in plasma cholesterol by the use of the combination of Compound X and atorvastatin. Test method: To Hartley guinea pigs (5-week-old male), N = 12), diet RC-4 containing 0.05% cholesterol and 10% corn oil was supplied for 3 weeks, and was administered orally for 14 days, once a day, a dose of 10-mL / kg of the vehicle , Compound X (30 mg / kg) alone, atorvastatin (3, 10, 30 mg / kg) alone or in combination of atorvastatin (3, 10, 30 mg / kg) and Compound X (30 mg / kg). On the morning of the next day after administration 14, blood was collected, and total cholesterol was measured in the plasma.

Result of the test: Average ± standard error (N = 12). Conclusion: Through the use of the combination of Compound X and atorvastatin, an additional action of decreasing the total cholesterol level in the plasma was observed (P <0.01, bidirectional ANOVA method). Example 3: Effect of reduction in plasma cholesterol by use of the combination of Compound X and simvastatin. Test method: Hartley guinea pigs (5-week-old male, N = 12) were given an RC-4 diet containing 0.05% cholesterol and 10% corn oil for 3 weeks. weeks, and was administered orally for 14 days, once a day, a 10-mL / kg dose of the vehicle, Compound X (30 mg / kg) alone, simvastatin (10, 30, 100 mg / kg) alone or combination of simvastatin (10, 30, 100 mg / kg) and Compound X (30 mg / kg). On the morning of the next day after administration 14, blood was collected, and total cholesterol was measured in the plasma. Result of the test: Average ± standard error (N = 12). Conclusion: By the use of the combination of Compound X and simvastatin, an additional action of decrease in total cholesterol in plasma (P <0.01, bidirectional ANOVA method). Example 4: Influence of Compound X and atorvastatin on liver pathological change. Test method: Hartley guinea pigs (5-week-old male, N = 12) were given RC-4 diet containing 0.05% cholesterol and 10% corn oil for 3 weeks, and orally administered for 14 days , once a day, a 10-mL / kg vehicle dose, Compound X (30 mg / kg) alone, atorvastatin (30 mg / kg) alone or in combination of atorvastatin (30 mg / kg) and Compound X (30 mg / kg). On the morning of the next day after administration 14, the blood was collected, and the total cholesterol in the plasma was measured. In addition, the liver was removed and a pathological evaluation was made. Result of the test: Average ± standard error (N = 12). Conclusion. : The image of hepatic cell necrosis was observed in the atorvastatin treatment group while it was not recognized in the group of Compound X alone or group of Compound X and atorvastatin in combination. Example 5: Influence of Compound X and atorvastatin on the change of deviated enzymes of the liver Test method: To the Hartley guinea pigs (male 5 weeks of age, N = 12), the RC-4 diet containing 0.05% cholesterol is supplied. and 10% corn oil for 2 weeks, and was administered orally for 7 days, once a day, a dose of 5 ml / kg of the vehicle, atorvastatin (50 mg / kg) alone or combination of atorvastatin (50 mg / kg ) and Compound X (30 mg / kg). On the morning of the next day after administration 7, the blood was collected, and the aminine and aminotransferase aminotransferase concentrations of aspartate which are markers of hepatic toxicity in the plasma were measured.

Result of the test: Average ± standard error (N = 12). * P < 0.05 against vehicle group (Student's T test). #P < 0.05 against treatment group with Atorvastatin (Student's T test). Conclusion: A significant increase in plasma aspartate aminotransferase was observed in the atorvastatin treatment group. However, the increase in aminotransferase in the group of Compound X and atorvastatin in combination was not recognized. Example 6: Influence of Compound X and cerivastatin on the change of muscle deviated enzymes Test method: To the Hartley guinea pigs (male 5 weeks of age, N = 16), a dose of 5 ml / kg of the vehicle was administered , cerivastatin (1 mg / kg) alone or in combination cerivastatin (1 mg / kg) and Compound X (30 mg / kg) orally for 14 days, once a day. On the morning of the next day after administration 14, the blood was collected and the creatine kinase (CK) and myoglobin (Mb) phosphokinase, which are markers of muscle toxicity, were measured in the plasma. Result of the test: Average ± standard error (N = 16). ** P < 0.01 against vehicle, and ## P < 0.01 against monivation of cerivastatin by Student's T test. Conclusion: Significant increases in plasma creatine and myoglobin phosphokinase were observed in the cerivastatin treatment group. However, Compound X significantly improved the creatinine and myoglobin phosphokinase increases induced by cerivastatin alone, with a slight increase in the reducing effect of cholesterol. As evidenced by the above, by the combined use of SSI and the HMG-CoA reductase inhibitor, a superior prophylactic and / or therapeutic effect against hyperlipidemia can be obtained by overcoming the limitations of the HMG-CoA reductase inhibitor that can not be obtained. for a simple administration. The present inventors further found that by using Ezetimibe as a third adjunct ingredient, more superior prophylactic and / or therapeutic effects against hyperlipidemia can be obtained. Next, this three-drug combination effect will be demonstrated by illustration of the test results. Example 7: Reducing effect on plasma cholesterol by use in triple combination of Compound X, simvastatin and ezetimibe. Test method: Hartley guinea pigs (males 5 weeks of age, N = 6) were given RC-4 diet containing 0.05% cholesterol and 10% corn oil for 3 weeks, and orally administered for 14 weeks. days, once a day, a dose of 6-mL / kg of the vehicle, Compound X (30 mg / kg) alone, combination of simvastatin (30 mg / kg) and ezetimibe (0.15 mg / kg) or triple combination of simvastatin (30 mg / kg), ezetimibe (0.15 mg / kg) and Compound X (30 mg / kg). On the morning of the next day after administration 14, blood was collected, and total cholesterol was measured in the plasma. Result of the test: Average ± typical error (N = 6) Conclusion:! By using triple combination of Compound X, simvastatin and ezetimibe, it was observed that Compound X demonstrates an additional action of reduction of total cholesterol I in plasma (P <0.05, bidirectional ANOVA method). As is evident from the above results, it is possible to carry out a more effective prevention and / or treatment against hyperlipidemia by using a combination of three drugs of SSI, HMG-CoA reductase inhibitor and Ezetimibe.

Additionally, when the combined use of the three drugs is used, the specific administration form such as the method of administration and the dosage form of administration can be referred to the embodiment indicated above of using two combined SSI drugs and the HMG-CoA reductase inhibitor. Industrial Applicability By using a combination of SSI and the HMG-CoA reductase inhibitor in the present invention, hyperlipidemia of a mammal can be prevented and / or treated effectively. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, it is claimed as property contained in the following claims: 1. A method for preventing and / or treating hyperlipidemia characterized in that it comprises administering to a mammal affected with hyperlipidemia a combination of an effective amount of inhibitor of squalene synthase and inhibitor of HMG-CoA reductase.
2.- The method according to the claim 1, characterized in that the HMG-CoA reductase inhibitor is administered at a high dose in an accepted dose.
3.- The method in accordance with the claim 2, characterized in that the HMG-CoA reductase inhibitor is administered at a maximum dose in the accepted dose.
4. A method for preventing and / or treating liver toxicity caused by administration of HMG-CoA reductase inhibitor, characterized in that it comprises the administration of an effective amount of squalene synthase inhibitor to inhibit the toxicity caused by the administration of the inhibitor of HMG-CoA reductase. HMG-CoA reductase to a mammal to which the HMG-CoA reductase inhibitor had been administered.
5. The method according to claim 4, characterized in that the mammal is affected with hyperlipidemia.
6. The method according to claim 1 or 4, characterized in that the squalene synthase inhibitor I I is a compound represented by the formula: wherein, Ri is a hydrogen atom or an optionally substituted hydrocarbon group, R 2 and R are the same or different and a hydrogen atom, optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X 'is a group comprising a carboxyl group optionally esterified, an optionally substituted carbamoyl group, an optionally substituted hydroxy group, an optionally substituted amino group or an optionally substituted heterocyclic residue having a hydrogen atom that can be deprotonated, ring A is an optionally substituted benzene ring or a heterocyclic Ring optionally substituted, Ring J 'is a 7 or 8 membered heterocyclic ring containing 3 heteroatoms or less as ring constituents, and Ring J' may have a substituent in addition to Ri, R2, R and X '.
7. - The method according to claim 1 or 4, characterized in that the squalene synthase inhibitor is N- [[(3R, 5S) -1- (3-acetoxy-2, 2-dimethylpropyl) -7-chloro-5 acid - (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidin-4-acetic acid.
8. - The method of compliance with the claim 1 or 4, characterized in that the HMG-CoA reductase inhibitor is one or more drugs selected from the group consisting of atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, cerivastatin and pitavastatin.
9. - The method according to claim 1 or 4, characterized in that the mammal affected with hyperlipidemia is a patient without tolerance to the HMG-CoA reductase inhibitor.
10.- The method according to the claim 1 or 4, characterized in that the mammal affected with hyperlipidemia is a high-risk patient with ischemic heart disease.
11. The method according to claim 1 or 4, characterized in that the mammal affected with hyperlipidemia is a patient affected with familial hypercholesterolemia.
12. A pharmaceutical composition for the prevention and / or treatment of hyperlipidemia, characterized in that it comprises the combination of an effective amount of inhibitor of squalene synthase and the HMG-CoA reductase inhibitor.
13. A pharmaceutical composition for the prevention and / or treatment of hyperlipidemia, characterized in that it comprises an effective amount of squalene synthase inhibitor and of the HMG-CoA reductase inhibitor that is formed in compounds or is packaged to be administered in divided doses, sequentially or simultaneously to a mammal affected with hyperlipidemia.
14. The pharmaceutical composition according to claim 12 or 13, characterized in that it comprises combining it with a high dose in the accepted dosage of HMG-CoA reductase inhibitor.
15. The pharmaceutical composition according to claim 12 or 13, characterized in that it comprises the combination with a maximum dose in the accepted dose of the HMG-CoA reductase inhibitor. 1 ,
16. - A method for improving an effect of prevention and / or treatment of hyperlipidemia for an inhibitor of HMGCoA reductase, characterized in that it comprises the administration of an effective amount of squalene synthase inhibitor to a mammal affected with hyperlipidemia wherein an effective amount of HMG-CoA reductase inhibitor.
17. The use of squalene synthase inhibitor for the manufacture of a pharmaceutical composition to prevent and / or treating hyperlipidemia, which comprises the combination of an effective amount of squalene synthase inhibitor and the HMG-CoA reductase inhibitor.
18. The use of squalene synthase inhibitor for the manufacture of a pharmaceutical composition for preventing and / or treating hyperlipidemia, comprising an effective amount of squalene synthase inhibitor and the HMG-CoA reductase inhibitor which are compounds or packaged to be administered in divided doses, sequentially or simultaneously to a mammal affected with hyperlipidemia.
19. The method according to claim 1 or 4, characterized in that an effective amount of ezetimibe in combination is also administered as a third drug.
20. The pharmaceutical composition according to claim 12 or 13, characterized in that it also comprises the combination of an effective amount of ezetimibe as a third drug.
21. The use of squalene synthase inhibitor for the manufacture of a pharmaceutical composition for preventing and / or treating hyperlipidemia according to claim 17 or 18, further comprising the combination of an effective amount of ezetimibe as a third drug.